Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient

ABSTRACT

A compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof: 
     
       
         
         
             
             
         
       
     
     (wherein each symbol is as defined in the description.) The compounds represented by formula (I) has the antagonistic activity against CCR5, so they are useful in preventing and/or treating CCR5-related diseases, for example, various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory bowel disease such as ulcerative colitis, etc.), immunological diseases (autoimmune diseases, rejection in organ transplantation (rejection of graft of solid organ, rejection of graft of pancreatic islet cells in therapy for diabetes, graft-versus-host disease, etc.), immunosuppression, psoriasis, multiple sclerosis, etc.), infectious diseases (infection with human immunodeficiency virus, acquired immunodeficiency syndrome, infection with RSV, etc.), allergic diseases (atopic dermatitis, urticaria, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, etc.), cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury, etc.), acute respiratory distress syndrome, shock accompanying bacterial infection, diabetes, cancer metastasis and so on.

TECHNICAL FIELD

The present invention relates to a nitrogen-containing heterocyclicderivative which is useful as medicament and a drug containing the sameas the active ingredient.

Explaining in more detail about the present invention, it relates to

(1) a compound represented by formula (I)

(wherein all symbols have the same meanings as described hereinafter), asalts thereof, an N-oxide thereof or a solvate thereof, or prodrugsthereof,(2) treatment and/or prevention for CCR5-related diseases comprisingcompounds represented by formula (I), a salt thereof, an N-oxide thereofor a solvate thereof, or prodrugs thereof, as an active ingredient, and(3) a process for the preparation thereof.

BACKGROUND OF THE INVENTION

Chemokine is known as an endogeneous basic protein having leukocytechemotactic and activating abilities and strong heparin-bindingabilities. At present, it is considered that chemokine is related to notonly the control of infiltration of specific leukocyte at the time ofinflammations and immune responses but also the development and homingof lymphocyte under physiological conditions and migration of hemocyteprecursor cells and somatic cells.

Differentiation, proliferation and cell death of hemocytes arecontrolled by various types of cytokine. In the living body,inflammations are found topically and differentiation, maturation andthe like of lymphocytes are carried out at certain specified sites. Thatis, various necessary cells migrate into certain specified sites andaccumulate therein to cause a series of inflammations and immuneresponses. Accordingly, migration of cells is also an indispensablephenomenon in addition to differentiation, proliferation and death ofcells.

Migration of hemocytes in the living body starts firstly in thedevelopment stage by the shift of hematopoiesis started in the AGMregion into permanent hematopoiesis in bone marrow via fetal liver.Furthermore, precursor cells of T cells and thymus dendritic cellsmigrate from the fetal liver into the bone marrow and then into thethymus gland and cytodifferentiate under thymus environment. The T cellwhich received clone selection migrates into secondary lymphoid tissuesand takes part in an immune response in the periphery. The Langerhans'cell of the skin activated and differentiated by capturing an antigenmigrates into the T cell region of a topical lymph node and activatesnaive T cell therein as a dendritic cell. The memory T cell performs itshoming again into the lymph node via lymphatic and blood vessels. Also,B cell, T cell in the intestinal epithelium, γδ T cell, NKT cell anddendritic cell migrate from bone marrow without passing through thethymus gland and differentiate to take part in an immune response.

Chemokine deeply takes part in the migration of such various cells.Chemokine receptors are greatly related to the control of inflammationand immune responses through a mechanism in which they are expressed atcertain specified periods in variously specific cells and the effectorcells are accumulated in a region where chemokine is produced.

For example, it is reported an investigation in animal models such asCCR5-knockout mouse suggesting that CCR5 as a chemokine receptor plays asignificant role in rejection in organ transplantation or autoimmunedisease, etc. (Transplantation, Vol. 72 (7), 1199-1205 (2001); Diabetes,Vol. 51 (8), 2489-2495 (2002); Journal of Virology, Vol. 77 (1), 191-198(2003); Journal of Immunology, Vol. 164 (12), 6303-6312 (2000)). It isalso reported which make a comparison a risk of developing severaldiseases and a length of the survival of the transplanted graft, etc.between a human having inactive CCR and a human having wild-type one(Ref. The Lancet, Vol. 357, 1758-1761 (2001); Arthritis & Rheumatism,Vol. 42 (5), 989-992 (1999); The Lancet, Vol. 354, 1264-1265 (1999);European Journal of Immunogenetics, Vol. 29 (6) 525-528 (2002)). It issuggested that CCR5 is related to several diseases, but they make noreference to the effect of drugs which antagonizes CCR in their reports.

At present, immunosuppressive treatment for diseases in transplantationarea is provided. That is, a calcineurin inhibitor such as cyclosporinor tacrolimus (FK506) is used mainly with various type of animmunosuppressant agent, for example, a TOR (target of rapamycin)inhibitor such as sirolimus (rapamycin), a non-specific antiphlogisticsuch as corticosteroids, an antiproliferative drug such as azathioprine,mycophenolate mofetil, etc. But, it frequently causes a chronicrejection or a severe side effect, so it is desired a useful novelimmunosuppressant agent which prolongs a length of the survival of thetransplanted graft and reduces the side effects in comparison withexisting drugs.

An antiinflammatory drug or a drug which modulates immune function suchas nonsteroidal antiinflammatory drug (NSAIDs) which have an inhibitoryactivity against cyclooxygenase (COX), disease modifying anti-rheumaticdrug (DMARDs), steroids, etc. is used for treatment for autoimmunedisease or allergic diseases. The more effective a drug is, the severera side effect caused by it is, and it is suggested that the treatmentwith these drugs is not an underlying remedy for the disease, but a meresymptomatic treatment.

At the same time, acquired immunodeficiency syndrome (hereinafterreferred to as “AIDS”) which is induced by human immunodeficiency virus(hereinafter referred to as “HIV”) is one of the diseases of which theirtherapeutic methods are most earnestly desired in recent years. Onceinfection with HIV is completed in a CD4-positive cell which is aprincipal target cell, HIV repeats its proliferation in the body of thepatient and, sooner or later, completely destroys T cell which takescharge of the immunological function. During this process, theimmunological function is gradually reduced to cause fever, diarrhea,lymph node enlargement and the like various immunodeficiency conditionswhich are apt to cause complications with pneumocystis carinii pneumoniaand the like various opportunistic infections. Such conditions are theonset of AIDS, and it is well known that they induce and worsen Kaposisarcoma and the like malignant tumors.

As the recent preventive and/or therapeutic methods for AIDS, attemptshave been made to, e.g., (1) inhibit growth of HIV by the administrationof a reverse transcriptase inhibitor or a protease inhibitor and (2)prevent or alleviate opportunistic infections by the administration of adrug having immunopotentiation activity.

Helper T cells which take charge of the central of immune system aremainly infected with HIV. It is known since 1985 that HIV uses themembrane protein CD4 expressing on the membrane of T cells in theinfection (Cell, 52, 631 (1985)). The CD4 molecule is composed of 433amino acid residues, and its expression can be found in macrophages,some B cells, vascular endothelial cells, Langerhans' cells in skintissues, dendritic cells in lymphoid tissues, glia cells of the centralnervous system and the like, in addition to the mature helper T cells.However, since it has been revealed that the infection with HIV is notcompleted by the CD4 molecule alone, a possibility has been suggested onthe presence of factors other than the CD4 molecule, which are relatedto the infection of cells with HIV.

CCR5, which is a receptor of RANTES, MIP-1α and MIP-1β, is also used atthe time of the infection with a macrophage tropic (R5) HIV (Science,272, 1955 (1996)).

Accordingly, substances which can compete with CCR5 for HIV, or whichcan bind to HIV virus thus causing the virus unable to bind to CCR5,could become HIV infection inhibitors.

It is also reported a possibility that the CCR5 is used in the infectionwith Respiratory Syncytial Virus (hereinafter referred to as “RSV”).

It is reported that CCR5 are expressed in arteriosclerotic plaque, so itis considered that chemokine receptor modulators are also useful intreating cardiovascular diseases.

Based on the above, it is considered that chemokine (for example,RANTES, MIP-1α, MIP-1β, etc.) receptors, especially CCR5 are deeplyrelated to the inflammation, immunological diseases, infectious diseases(infection with HIV, infection with RSV, etc.), and cardiovasculardiseases. For example, it is considered that they are related to variousinflammatory diseases (asthma, nephritis, nephropathy, hepatitis,arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatorybowel disease such as ulcerative colitis, etc.), immunological diseases(autoimmune diseases, rejection in organ transplantation (rejection ofgraft of solid organ, rejection of graft of pancreatic islet cells intherapy for diabetes, graft-versus-host disease, etc.),immunosuppression, psoriasis, multiple sclerosis, etc.), infectiousdiseases (infection with human immunodeficiency virus, acquiredimmunodeficiency syndrome, infection with RSV, etc.), allergic diseases(atopic dermatitis, urticaria, allergic bronchopulmonary aspergillosis,allergic eosinophilic gastroenteritis, etc.), cardiovascular diseases(arteriosclerosis, ischemic reperfusion injury, etc.), acute respiratorydistress syndrome, shock accompanying bacterial infection, diabetesmellitus, cancer metastasis and the like.

It is reported that the aminopiperidine derivatives represented byformula (Z)

(wherein R^(1Z) is hydrogen atom or C1-12 alkyl, R^(2z) and R^(3Z) areeach independently hydrogen atom or C1-12 alkyl, X^(Z) is nitrogen atomor oxygen atom, A^(Z) is

(wherein R^(4Z) is hydrogen atom, C1-12 alkyl, C3-8 cycloalkyl, aryl,substituted aryl, aryl-C(═O)— or aryl-CH(OH)—, R^(5Z) is hydrogen, C1-12alkyl, C1-4 alkoxy, halogen or COR, R^(6Z) is hydrogen, C1-12 alkyl orsubstituted C1-4 alkyl. With the proviso that the definition of eachsymbol is an excerpt partially) are useful as inhibitors of thechemokine receptors (ref. specification of WO02/079186).

It is described that the sulfonic acid compounds represented by formula(W)

(wherein X^(W) is —O—, —S—, —CH₂— or —NR⁶—, Y^(W) is C6-10 aryl or C2-9heteroaryl, R^(1W) is selected from the group consisting of H—, HO—,halo-, C1-8 alkyl-optionally substituted with 1-3 fluorine atoms, etc.,R^(2W) and R^(3W) is selected from the group consisting of H—, oxo, C1-8alkyl-optionally substituted with 1-3 fluorine atoms, etc., R^(4W) isselected from the group consisting of: H—, HO—, halo-, NC—, etc., R^(5W)is C1-8 alkyl, aW is 0-5, bW is 0-2, cW is 0-2, and dW is 0-4. With theproviso that the definition of each symbol is an excerpt partially),pharmacological acceptable salts thereof and prodrugs thereof areselective antagonists of CCR1 (ref specification of WO02/102787).

Moreover, 1-(4-pyridyl)-piperazine derivatives are described as CCR5antagonists (ref specification of U.S. Pat. No. 6,391,865).

On the other hand, it is reported that triazaspiro[5.5]undecanederivatives, quaternary ammonium salts thereof or N-oxides thereof, orpharmacologically acceptable salts thereof regulate the effect ofchemokine/chemokine receptor, so they are used for prevention and/ortreatment of various inflammatory diseases, asthma, atopic dermatitis,urticaria, allergic diseases (allergic bronchopulmonary aspergillosis orallergic eosinophilic gastroenteritis etc.), nephritis, nephropathy,hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis,conjunctivitis, ischemic reperfusion disorder, multiple sclerosis,ulcerative colitis, acute respiratory distress syndrome, cytotoxicshock, diabetes, autoimmune disease, in transplanted organ rejectionreactions, immunosuppression, cancer metastasis and acquired immunedeficiency syndrome (ref. specification of WO01/40227).

It is described that the compounds represented by formula (M)

(wherein mM and nM, which are the same or different, is each zero or theinteger 1 or 2, Alk^(3M) is a covalent bond or a straight or branchedC1-6 alkylene chain, R^(1M) and R^(2M), which are the same or different,is each a hydrogen atom or a straight or branched C1-6 alkyl group,D^(M) is an optionally substituted aromatic or heteroaromatic ringgroup, E^(M) is an optionally substituted C7-10 cycloalkyl, C7-10cycloalkenyl or C7-10 polycycloaliphatic group) are modulators of CXCR3(ref. specification of WO03/070242).

DISCLOSURE OF THE INVENTION

The compound which has the antagonistic activity against CCR5 is usefulin preventing and/or treating CCR5-related diseases. Therefore it isdesired that safety CCR5 antagonists are developed.

In order to find a compound which specifically binds chemokine receptor,especially CCR5, and has the antagonistic activity against it, thepresent inventors have conducted intensive studies and found, as aresult, that the objects can be accomplished by the compound representedby formula (I), and thus the present invention has been accomplished.

The present invention relates to

1. a compound represented by formula (I)

wherein R¹ represents (1) —N(R^(1A))SO₂—R^(1B), (2) —SO₂NR^(1C)R^(1D),(3) —COOR^(1E), (4) —OR^(1F), (5) —S(O)_(m)R^(1G), (6) —CONR^(1H)R^(1J),(7) —NR^(1K)COR^(1L), or (8) cyano, wherein m is 0, 1 or 2; R^(1A),R^(1B), R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K)and R^(1L) each independently represents a hydrogen atom, a hydrocarbongroup which may have a substituent(s), or a 3- to 15-memberedheterocyclic group which may have a substituent(s), and wherein R^(1C)and R^(1D) or R^(1H) and R^(1J) may form a nitrogen-containingheterocyclic group which may have a substituent(s) together with anitrogen atom to which they bind;

X and Y each independently represents a bond or a spacer containing 1 to3 atoms as a main chain;

ring A and ring B, which are the same or different, each represents a 3-to 15-membered carbocyclic group or heterocyclic group which may have asubstituent(s);

ring D is a 3- to 15-membered nitrogen-containing heterocyclic groupwhich may have a substituent(s);

R² is (1) a hydrogen atom, (2) a hydrocarbon group which may have asubstituent(s), (3) a cyano group, (4) a hydroxy group which may beprotected, (5) an amino group which may have a substituent(s), (6) anoxo group, (7) a 3- to 15-membered heterocyclic group which may have asubstituent(s) or (8) ═N—OR⁶, wherein R⁶ represents a hydrogen atom orC1-4 alkyl,

a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrugthereof;

2. the compound according to the above-described 1, wherein X and Y areeach independently a bond or a divalent group comprising a combinationof one or two unit(s) selected from (1) —CR⁷R⁸—, (2) —NR⁹—, (3) —CO—,(4) —O—, (5) —S—, (6) —SO—, (7) —SO₂— and (8) —C(═N—OR¹⁰)—, wherein R⁷and R⁸ each independently represents a hydrogen atom, C1-4 alkyl, —OR¹¹or phenyl, R⁹ represents a hydrogen atom, C1-4 alkyl, or phenyl; R¹⁰ andR¹¹ each independently represents a hydrogen atom or C1-4 alkyl;3. the compound according to the above-described 2, wherein X is a bond,—O— or —CH₂—;4. the compound according to the above-described 2, wherein Y is C1-2alkylene;5. the compound according to the above-described 1, wherein ring D is a5- to 10-membered nitrogen-containing heterocyclic group which may havea substituent(s);6. the compound according to the above-described 5, wherein ring D is atropane, pyrrolidine, piperidine or azepane ring which may have asubstituent(s);7. the compound according to the above-described 6, wherein ring D is apiperidine ring which may have a substituent(s);8. the compound according to the above-described 1, wherein ring A andring B, which are the same or different, are each a 5- or 6-memberedaromatic ring group which may have a substituent(s);9. the compound according to the above-described 1, wherein R² is

wherein the arrow represents a binding position to ring D, R⁵¹, R⁵² andR⁵³ each independently represents (1) a hydrogen atom, (2) a hydrocarbongroup which may have a substituent(s), (3) a 3- to 15-memberedheterocyclic group which may have a substituent(s), (4) a C1-4 alkoxygroup which may have a substituent(s), (5) a phenoxy group which mayhave a substituent(s) or (6) a benzyloxy group which may have asubstituent(s);10. the compound according to the above-described 1, wherein R² is

wherein the arrow represents a binding position to ring D, R⁵¹ and R⁵⁴each independently represents (1) a hydrogen atom, (2) a hydrocarbongroup which may have a substituent(s), (3) a 3- to 15-memberedheterocyclic group which may have a substituent(s), (4) a C1-4 alkoxygroup which may have a substituent(s), (5) a phenoxy group which mayhave a substituent(s) or (6) a benzyloxy group which may have asubstituent(s);11. the compound according to the above-described 1, which isrepresented by formula (Ib)

wherein all symbols have the same meanings as those described in theabove-described 1 and 9;12. the compound according to the above-described 9, wherein thehydrocarbon group which may have a substituent(s) or the 3- to15-membered heterocyclic group which may have a substituent(s)represented by R⁵¹ is an aromatic ring group which may have asubstituent(s);13. the compound according to the above-described 12, wherein thearomatic ring group which may have a substituent(s) is a benzene,pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, oxazole, isoxazole, thiazole, isothiazole,furazan, oxadiazole, or thiadiazole ring;14. the compound according to the above-described 12, which isrepresented by formulae (Ie), (If), (Ig), or (Ih)

wherein symbol

represents β-configuration and symbol

represents α-configuration, β-configuration or the mixture of them; R⁵⁶is aromatic ring group which may have a substituent(s); other symbolshave the same meanings as those described in the above-described 1 and9;15. the compound according to the above-described 1, wherein thehydrocarbon group which may have a substituent(s) represented by R⁵¹ isC1-15 alkyl;16. the compound according to the above-described 15, which is selectedfrom the group consisting of

-   (1)    5-({[butyl(1-{4-[4-(methylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,-   (2)    5-[({butyl[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,-   (3)    5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,-   (4)    5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,-   (5)    5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2-chloro-4-fluorobenzamide,-   (6)    2-(5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorophenyl)acetamide,-   (7)    5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-methylbenzamide,-   (8)    5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,    and-   (9)    5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide;    17. the compound according to the above-described 12, wherein the    aromatic ring group represented by R⁵¹ is a mono-carbocyclic group    or mono-heterocyclic group which have aromaticity;    18. the compound according to the above-described 17, which is    selected from the group consisting of-   (1)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,-   (2)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (3)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (4)    N-[4-({5-[(4-{3-thienyl[(3-thienylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,-   (5)    2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (6)    N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]phenyl}methanesulfonamide,-   (7)    4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]-N-[2-(4-morpholinyl)ethyl]benzenesulfonamide,-   (8)    N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (9)    2-chloro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (10)    N-(4-{[5-({4-[({[4-chloro-3-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (11)    2-fluoro-5-{[((3-fluorophenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide,-   (12)    N-(3-fluorophenyl)-N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea,-   (13)    2-[4-({4-[[({4-fluoro-3-[(methylsulfonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,-   (14)    2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (15)    2-fluoro-N-methyl-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,-   (16)    2-[4-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino)benzamide,-   (17)    N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamid,-   (18)    N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide,-   (19)    N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,    and-   (20)    N′-(4-fluorophenyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]pyridin-3-yl}methyl)piperidin-4-yl]-N-phenylurea;    19. the compound according to the above-described 11, which is    selected from a group the group consisting of:-   (1)    2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (2)    N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (3)    N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide,    and-   (4)    N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide;    20. the compound according to the above-described 11, which is    selected from the group consisting of-   (1)    5-[({butyl[1-(4-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,-   (2)    N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,-   (3)    N-(4-{[5-({4-[{[(4-methylphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (4)    N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,    and-   (5)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acetamide;    21. the compound according to the above-described 1, which is    selected from the group consisting of:-   (1)    2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (2)    N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide    dihydrochloride,-   (3)    N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide    hydrochloride,-   (4)    N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide    dihydrochloride,-   (5)    5-[({butyl[1-(4-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide    hydrochloride,-   (6)    N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide    hydrochloride,-   (7)    N-(4-{[5-({4-[{[(4-methylphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (8)    N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,    and-   (9)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acetamide    hydrochloride;    22. a pharmaceutical composition, which comprises the compound    according to the above-described 1, a salt thereof, an N-oxide    thereof, a solvate thereof, or a prodrug thereof;    23. the pharmaceutical composition according to the above-described    22, which is a chemokine receptor antagonist;    24. the pharmaceutical composition according to the above-described    23, which is a CCR5 antagonist;    25. the pharmaceutical composition according to the above-described    24, which is an agent for treatment and/or prevention for a    CCR5-related disease;    26. the pharmaceutical composition according to the above-described    25, wherein the CCR5-related disease is infectious diseases,    immunological diseases, inflammatory diseases and/or cardiovascular    diseases;    27. the pharmaceutical composition according to the above-described    26, wherein the CCR5-related disease is infection with human    immunodeficiency virus, acquired immunodeficiency syndrome,    infection with Respiratory Syncytial Virus, rejection in organ    transplantation, multiple sclerosis, inflammatory bowel disease,    and/or asthma;    28. the pharmaceutical composition according to the above-described    26, wherein the immunological diseases is rejection in organ    transplantation;    29. the pharmaceutical composition according to the above-described    22, which is an agent for prevention and/or treatment for infectious    diseases, immunological diseases, inflammatory diseases and/or    cardiovascular diseases;    30. a medicament comprising a combination of the compound    represented by formula (I) according to the above-described 1, a    salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug    thereof, and one or more agent(s) selected from a reverse    transcriptase inhibitor, a protease inhibitor, an integrase    inhibitor, a CCR2 antagonist, a CCR3 antagonist, a CCR4 antagonist,    a CCR5 antagonist, a CXCR3 antagonist, a CXCR4 antagonist, a fusion    inhibitor, an antibody against a surface antigen of HIV, and a    vaccine of HIV;    31. a medicament comprising a combination of the compound    represented by formula (I) according to the above-described 1, a    salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug    thereof, and one or more agent(s) selected from an immunosuppressant    agent, a nonsteroidal antiinflammatory drug, a disease modifying    anti-rheumatic drug, steroids, an antiinflammatory enzyme    preparations, a chondroprotective agents, a T-cell inhibitor, a TNFα    inhibitor, a prostaglandin synthase inhibitor, an IL-1 inhibitor, an    IL-6 inhibitor, an interferon gamma agonist, prostaglandins, a    phosphodiesterase inhibitor, and a metalloproteinase inhibitor;    32. a method for preventing or treating a CCR5-related disease in a    mammal, which comprises administering to a mammal an effective    amount of a compound represented by formula (I) according to the    above-described 1, a salt thereof; an N-oxide thereof, a solvate    thereof, or a prodrug thereof;    33. use of a compound represented by formula (I) according to the    above-described 1, a salt thereof, an N-oxide thereof, a solvate    thereof, or a prodrug thereof for the manufacture of an agent for    prevention and/or treatment of a CCR5-related disease;    34. a pharmaceutical composition according to the above-described    22, which is an inhibitor of cell migration; and    35. a process for preparation of the compound represented by    formula (I) according to the above-described 1, a salt thereof, an    N-oxide thereof or a solvate thereof, or a prodrug thereof.

The “hydrocarbon group” in the “hydrocarbon group which may have asubstituent(s)” represented by R^(1A), R^(1B), R^(1C), R^(1D), R^(1E),R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) and R^(1L) includes, for example,(a) C1-15 alkyl such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl etc.; (b) C3-8cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyletc.; (c) C2-10 alkenyl such as vinyl, allyl, 2-methylallyl, 2-butenyl,3-butenyl, 3-octenyl etc.; (d) C2-10 alkynyl such as ethynyl,2-propynyl, 3-hexynyl etc.; (e) C3-10 cycloalkenyl such ascyclopropenyl, cyclopentenyl, cyclohexenyl etc.; (f) C6-14 aryl such asphenyl, naphthyl etc., (g) C7-16 aralkyl such as benzyl, phenylethyletc.; (h) (C3-8 cycloalkyl)-(C1-4 alkyl) such as cyclohexylmethyl,cyclohexylethyl, cyclohexylpropyl, 1-methyl-1-cyclohexylmethyl,cyclopropylethyl etc.

The “3- to 15-membered heterocycle” in the “3- to 15-memberedheterocyclic group which may have a substituent(s)” represented byR^(1A), R^(1B), R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J),R^(1K) and R^(1L) includes a “3- to 15-membered unsaturated heterocycle”or a “3- to 15-membered saturated heterocycle”.

The “3- to 15-membered unsaturated heterocycle” includes, for example,pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, beta-carboline, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine,pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline,dihydropyridine, tetrahydropyridine, dihydropyrazine,tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine,dihydropyridazine, tetrahydropyridazine, dihydroazepine,tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrofuran,dihydropyran, dihydrooxepine, tetrahydrooxepine, dihydrothiophene,dihydrothiopyran, dihydrothiepine, tetrahydrothiepine, dihydrooxazole,dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazan,dihydrooxadiazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran,dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene,dihydroindazole, dihydroquinoline, tetrahydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine,pyrazinomorpholine, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine,dihydrobenzodiazepine, tetrahydrobenzo diazepine, benzodioxepane,dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole,tetrahydrocarbazole, dihydroacridine, tetrahydroacridine,dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, dioxaindan, benzodioxane, chroman,benzodithiolane, benzodithiane etc.

The “3- to 15-membered saturated heterocycle” includes, for example,aziridine, azetidine, azocane, pyrrolidine, imidazolidine, triazolidine,tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine,perhydropyridazine, azepane (perhydroazepine), perhydrodiazepine,oxirane, oxetane, tetrahydrofuran, tetrahydropyran, perhydrooxepine,thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran,perhydrothiepine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole(isoxazolidine), tetrahydrothiazole (thiazolidine),tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan,tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine,tetrahydrooxadiazine, perhydrooxazepine, perhydrooxadiazepine,tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine,tetrahydrothiadiazine, perhydrothiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, oxathiane, perhydrobenzofuran,perhydroisobenzofuran, perhydrobenzothiophene,perhydroisobenzothiophene, perhydro indazole, perhydroquinoline,perhydroisoquinoline, perhydrophthalazine, perhydronaphthyridine,perhydroquinoxaline, perhydroquinazoline, perhydrocinnoline,perhydrobenzoxazole, perhydrobenzothiazole, perhydrobenzimidazole,perhydrocarbazole, perhydroacridine, perhydrodibenzofuran,perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane,

The “substituents” in the “hydrocarbon group which may have asubstituent(s)” or 3- to 15-membered heterocyclic group represented byR^(1A), R^(1B), R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J),R^(1K) and R^(1L) include, for example, (1) nitro, (2) hydroxy group,(3) oxo, (4) thioxo, (5) cyano, (6) carbamoyl, (7) aminocarbonylsubstituted by C1-8 hydrocarbon substituted by one or two substituent(s)selected from (a) hydroxyl, (b) amino, (c) C1-4 alkoxy, (d) mono- ordisubstituted amino substituted by C1-8 hydrocarbon group, etc., (e)carboxyl, (f) C1-6 alkoxy-carbonyl etc. (e.g., N-methylaminocarbonyl,N-ethylaminocarbonyl, N-propylamino carbonyl, N-butylaminocarbonyl,N-cyclohexylmethylaminocarbonyl, N,N-dimethylaminocarbonyl,N-butyl-N-cyclohexylmethylaminocarbonyl, N-cyclohexylaminocarbonyl,phenylaminocarbonyl, N-(2-methoxyethyl)aminocarbonyl,N-(2-hydroxyethyl)aminocarbonyl, N-(2-aminoethyl)aminocarbonyl,N-[2-(N′,N′-dimethylamino)ethyl]amino carbonyl,N-(2-carboxyethyl)aminocarbonyl,N-(2-methoxycarbonylethyl)aminocarbonyl, etc.), (8) carboxy, (9) C1-6alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, etc., (10) sulfo, (11) halogen such as fluorine,chlorine, bromine or iodine, (12) C1-6 alkoxy which may be substitutedby halogen (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, difluoromethoxy or trifluoro,ethoxy), (13) phenoxy, (14) halogenophenoxy such as o-, m- orp-chlorophenoxy, or o-, m- or p-bromophenoxy etc., (15) C1-6 alkylthiosuch as methylthio, ethylthio, propylthio, isopropylthio, butylthio,tert-butylthio etc., (16) phenylthio, (17) C1-6 alkylsulfinyl such asmethylsulfinyl ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc., (18)C1-6 alkylsulfonyl such as methylsulfonyl or ethylsulfonyl,propylsulfonyl, butylsulfonyl, etc., (19) amino, (20) C1-6 loweracylamino such as acetylamino or propionylamino etc., (21) mono- ordisubstituted amino substituted by hydrocarbon group (the “hydrocarbongroup” has the same meanings as above “hydrocarbon group” and may besubstituted by oxo, amino which may be substituted by optionalsubstituents (e.g., hydrocarbon), carbamoyl, halogen or hydroxy groupetc.) (e.g., methylamino, ethylamino, propylamino, isopropylamino,butylamino, dimethylamino, diethylamino, cyclohexylamino,1-carbamoyl-2-cyclohexylethylamino, N-butyl-N-cyclohexylmethylamino orphenylamino etc.), (22) C1-8 alkanoyl such as formyl or acetyl,propionyl, butyryl, isobutyryl, cyclohexylcarbonyl, etc., (23) C6-10aryl-C1-4 lower acyl such as benzoyl, benzylcarbonyl, (24) 3- to15-membered heterocyclic group, which includes 1 to 4 hetero atomsselected from oxygen, sulfur and nitrogen besides carbon atom, andoptionally has 1 to 4 substituents selected from (a) halogen such asbromine, chlorine, or fluorine, (b) hydrocarbon optionally substitutedby oxo or hydroxy group etc., (the “hydrocarbon group” has the samemeanings as above “hydrocarbon group”) such as methyl, ethyl, propyl,isopropyl, benzyl, cyclohexyl, cyclohexylmethyl or cyclohexylethyl etc.,(c) halogenophenoxy such as o-, m- or p-chlorophenoxy, or o-, m- orp-bromophenoxy etc., and (d) oxo etc., such as thienyl, furyl,pyrazolyl, tetrahydropyranyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyromidinyl,pyridazinyl, quinolyl, isoquinolyl, indolyl, aziridinyl, azetidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolidinyl, piperidino,morpholino, dihydropyridyl, N-methylpiperazinyl, N-ethylpiperazinyletc., (25) C1-10 haloalkyl such as difluoromethyl, trifluoromethyl,trifluoroethyl, chloromethyl, dichloromethyl, or trichloroethyl etc.,(26) hydroxyimino, (27) alkyloxyimino such as methyloxyimino orethyloxyimino etc., (28) alkyl sulfonylamino such asmethylsulfonylamino, ethylsulfonylamino or benzylsulfonylamino etc., or(29) arylsulfonylamino such as phenylsulfonylamino orp-toluenesulfonylamino etc., (30) cyclic aminocarbonyl such as1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl,1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyletc., (31) C1-8 hydrocarbon group substituted by 1 or 2 substituentsselected from (a) hydroxy, (b) amino, (c) C1-4 alkoxy, (d) mono- ordisubstituted amino substituted by C1-8 hydrocarbon group, etc., (e)aminocarbonyl substituted by C1-8 hydrocarbon group, etc. which may havea substituent(s) (This substituents are selected from, for example, (a)hydroxy, (b) amino, (c) C1-4 alkoxy, (d) mono- or disubstituted aminosubstituted by C1-8 hydrocarbon group, etc., (e) carboxy, (f) C1-6alkoxy-carbonyl, and may have 1 or 2 group(s)), such as hydroxymethyl,hydroxyethyl, aminomethyl, methoxymethyl, N,N-dimethylaminomethyl,carbamoylmethyl, N-methylaminovarbonylmethyl,N,N-dimethylaminocarbonylmethyl, etc., (32) (C1-4 alkoxy)-(C1-4 alkyl)group such as methoxyethyl etc., (33) C1-8 alkanoyloxy group such asformyloxy, acetyloxy, propyonyloxy, butyryloxy, isobutyryloxy orcyclohexylcarbonyloxy etc., or benzoyloxy group, (34) amidino group,(35) imino group, (36) C1-8 alkanoylamide group such as formamide,acetamide, trifluoroacetamide, propionylamide, butyrylamide,isobutyrylamide, cyclohexylcarbonylamino etc., (37) benzamide group,(38) carbamoylamino group, (39) N—C1-4 alkylcarbamoylamino group such asN-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino,N-isopropylcarbamoylamino, N-butylcarbamoylamino etc., (40) N,N-di-C1-4alkylcarbamoylamino group such as N,N-dimethylcarbamoylamino,N,N-diethylcarbamoylamino, N,N-dipropylcarbamoylamino,N,N-dibutylcarbamoylamino etc., (41) C1-3 alkylenedioxy group such asmethylenedioxy or ethylenedioxy etc., (42) —B(OH)₂, (43) epoxy group,(44) mercapto group, (45) sulfino group, (46) phosphono group, (47)sulfamoyl group, (48) C1-6 monoalkylsulfamoyl such as N-methylsulfamoyl,N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl orN-butylsulfamoyl etc., (49) di-C1-4 alkylsulfamoyl group such asN,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl orN,N-dibutylsulfamoyl etc., (50) phenylsulfinyl group, (51)phenylsulfonyl group, (52) azide group, or (53) hydrocarbon group (This“hydrocarbon group” have the same meanings as the above-described“hydrocarbon group”, for example, methyl, ethyl, propyl, isopropyl,vinyl, ethynyl, cyclohexenyl, phenyl, naphthyl, benzyl, cyclohexyl,cyclohexylmethyl, cyclohexylethyl, etc.). The “hydrocarbon group whichmay have a substituent(s)” or “3- to 15-membered heterocyclic groupwhich may have a substituent(s)” can have 1 to 10 of substituentsselected from above (1) to (53). When the number of substituents is twoor more, each substituent may be same or different.

The “nitrogen-containing heterocyclic group” in the “nitrogen-containingheterocyclic group which may have a substituent(s)” formed by R^(1C) andR^(1D) or R^(1H) and R^(1J) together with a nitrogen atom to which theybind include, for example, aziridine, azetidine, pyrroline, pyrrolidine,imidazoline, imidazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,perhydropyrimidine, perhydropyridazine, tetrahydroazepine, azepane(perhydroazepine), tetrahydrodiazepine, perhydrodiazepine,tetrahydrooxazole (oxazolidine), tetrahydrothiazole (thiazolidine),tetrahydrooxazine, perhydrooxazepine, tetrahydrothiazine,perhydrothiazepine, morpholine, thiomorpholine ring, etc.

The “substituents” in the “nitrogen-containing heterocyclic group whichmay have a substituent(s)” formed by R^(1C) and R^(1D) or R^(1H) andR^(1J) together with a nitrogen atom to which they bind include have thesame meanings as the “substituents” in the “hydrocarbon group which mayhave a substituent(s)” or “3- to 15-membered heterocyclic group whichmay have a substituent(s)” has the same meaning as the “hydrocarbongroup which may have a substituent(s)” represented by R^(1A), R^(1B),R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) andR^(1L).

The “spacer containing 1 to 3 atoms as a main chain” represented by Xand Y means a space formed by 1 to 3 continued atoms of a main chain. Inthis case, the “number of atoms as a main chain” should be counted suchthat the number of atoms as a main chain becomes minimized. The “spacerhaving from 1 to 3 atoms as a main chain” include, for example, abivalent group comprising 1 to 3 selected from —CR⁷R⁸—, —NR⁹—, —CO—,—O—, —S—, —SO—, —SO₂— and —C(═N—OR¹⁰)— (wherein R⁷ and R⁸ are eachindependently hydrogen atom, C1-4 alkyl, —OR¹¹ or phenyl, R⁹ is hydrogenatom, C1-4 alkyl or phenyl, R¹⁰ and R¹¹ are each independently hydrogenatom or C1-4 alkyl). In the case, the “C1-4 alkyl” represented by R⁷ toR¹⁰ includes, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl etc. Concretely, the “spacer having from1 to 3 atoms as a main chain” include, for example, —CR⁷R⁸—, —NR⁹—,—CO—, —O—, —S—, —C(═N—OR¹⁰)—, —NR⁹CO—, —CONR⁹—, —NR⁹COCR⁷R⁸— or—CONR⁹CR⁷R⁸— (wherein R⁷-R¹⁰ have the same meanings as described above).

“C1-2 alkylene” represented by Y is methylene or ethylene.

The “3- to 15-membered carbocyclic group” in the “3- to 15-memberedcarbocyclic group or heterocyclic group which may have a substituent(s)”represented by ring A and ring B includes, for example, a “3- to15-membered cyclic hydrocarbon” etc. The “cyclic hydrocarbon” in the “3-to 15-membered cyclic hydrocarbon” includes, for example, an“unsaturated cyclic hydrocarbon” or a “saturated cyclic hydrocarbon”.The “saturated cyclic hydrocarbon” includes, for example, cycloalkanesuch as cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane,cyclododecane, cyclotridecane, cyclotetradecane or cyclopentadecane etc;perhydropentalene; perhydroazulene; perhydroindene; perhydronaphthalene;perhydroheptalene; spiro[4.4]nonane; spiro[4.5]decane;spiro[5.5]undecane; bicyclo[2.2.1]heptane; bicyclo[3.1.1]heptane;bicyclo[2.2.2]octane; adamantane; noradamantane etc. The “unsaturatedcyclic hydrocarbon” includes, for example, cycloalkene such ascyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene or cyclooctadiene etc; benzene;pentalene; azulene; indene; indan; naphthalene; dihydronaphthalene;tetrahydronaphthalene; heptalene; biphenylene; as-indacene; s-indacene;acenaphthene; acenaphthylene; fluorene; phenalene; phenanthrene;anthracene; bicyclo[2.2.1]hept-2-ene; bicyclo[3.1.1]hept-2-ene;bicyclo[2.2.2]oct-2-ene etc.

The “3- to 15-membered heterocyclic group” in “3- to 15-memberedcarbocyclic group or heterocyclic group which may have a substituent(s)”represented by ring A and ring B have the same meanings as theabove-described “3- to 15-membered heterocyclic group” in “3- to15-membered heterocyclic group which may have a substituent(s)”represented by R^(1A), R^(1B), R^(1C), R^(1D), R^(1E), R^(1F), R^(1G),R^(1H), R^(1J), R^(1K) and R^(1L).

The “substituents” in “3- to 15-membered carbocyclic group orheterocyclic group which may have a substituent(s)” represented by ringA and ring B have the same meanings as the “substituents” in the“hydrocarbon group which may have a substituent(s)” or “3- to15-membered heterocyclic group which may have a substituent(s)”represented by R^(1A), R^(1B), R^(1C), R^(1D), R^(1E), R^(1F), R^(1G),R^(1H), R^(1J), R^(1K) and R^(1L). The 1 to 10 substituents may existwherever possible. When the number of substituents is two or more, eachsubstituent may be same or different.

The “5- or 6-membered aromatic ring group” in the “5- or 6-memberedaromatic ring group which may have a substituent(s)” represented by ringA and ring B, include, for example, benzene, pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, triazine, furan, thiophene, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole or thiadiazole ring etc.

The “substituents” in the “5- or 6-membered aromatic ring group whichmay have a substituent(s)” represented by ring A and ring B have thesame meanings as the “substituents” in the “hydrocarbon group which mayhave a substituent(s)” or “3- to 15-membered heterocyclic group whichmay have a substituent(s)” represented by R^(1A), R^(1B), R^(1C),R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) and R^(1L). The 1to 10 substituents may exist wherever possible. When the number ofsubstituents is two or more, each substituent may be same or different.

The “nitrogen-containing heterocyclic group” in the “3- to 15-memberednitrogen-containing heterocyclic group which may have a substituent(s)”represented by ring D refers to a heterocycle which may contain, inaddition to at least one nitrogen atom besides carbon atom, 1 to 3hetero atoms selected from nitrogen, oxygen and sulfur atoms. The “3- to15-membered nitrogen-containing heterocycle” includes a “3- to15-membered nitrogen-containing unsaturated heterocycle” and “3- to15-membered nitrogen-containing saturated heterocycle”.

The “3- to 15-membered nitrogen-containing unsaturated heterocyclicgroup” includes, for example, pyrrole, imidazole, triazole, tetrazole,pyrazole, indole, isoindole, indazole, purine, benzimidazole,benzoazepine, benzodiazepine, benzotriazole, carbazole, β-carboline,phenothiazine, phenoxazine, perimidine, pyrroline, imidazoline,triazoline, tetrazoline, pyrazoline, dihydropyridine,tetrahydropyridine, dihydropyrazine, tetrahydropyrazine,dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine,tetrahydropyridazine, dihydroazepine, tetrahydroazepine,dihydrodiazepine, tetrahydrodiazepine, dihydrooxazole, dihydroisoxazole,dihydrothiazole, dihydroisothiazole, dihydrofurazan, dihydrooxadiazole,dihydrooxazine, dihydro oxadiazine, dihydrooxazepine,tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine,dihydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,indoline, isoindoline, dihydroindazole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,dihydroquinazoline, tetrahydro quinazoline, dihydrocinnoline,tetrahydrocinnoline, dihydrobenzoxazine, dihydrobenzothiazine,pyrazinomorpholine, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzimidazole, dihydrobenzoazepine, tetrahydrobenzoazepine,dihydrobenzodiazepine, tetrahydrobenzodiazepine, dihydrobenzooxazepine,tetrahydrobenzooxazepine, dihydrocarbazole, tetrahydrocarbazole,dihydroacridine, tetrahydroacridine; or 3- to 15-memberednitrogen-containing saturated heterocyclic group includes, for example,aziridine, azetidine, azocane, pyrrolidine, imidazolidine, triazolidine,tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine,perhydropyridazine, azepane (perhydroazepine), perhydrodiazepine,tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine),tetrahydrothiazole (thiazolidine), tetrahydroisothiazole(isothiazolidine), tetrahydrofurazan, tetrahydrooxadiazole(oxadiazolidine), tetrahydrooxazine, tetrahydro oxadiazine,perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazole(thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine,tetrahydrothiazepine, perhydrothiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, perhydroindazole, perhydroquinoline,perhydroisoquinoline, perhydrophthalazine, perhydronaphthyridine,perhydroquinoxaline, perhydroquinazoline, perhydrocinnoline,perhydrobenzoxazole, perhydrobenzothiazole, perhydrobenzimidazole,perhydrocarbazole, perhydroacridine,

The “substituents” in the “3- to 15-membered nitrogen-containingheterocyclic group which may have a substituent(s)” represented by ringD have the same meanings as the “substituents” in the “hydrocarbon groupwhich may have a substituent(s)” or “3- to 15-membered heterocyclicgroup which may have a substituent(s)” represented by R^(1A), R^(1B),R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) andR^(1L). The 1 to 10 substituents may exist wherever possible. When thenumber of substituents is two or more, each substituent may be same ordifferent.

The “5- to 10-membered nitrogen-containing heterocyclic group” in the“5- to 10-membered nitrogen-containing heterocyclic group which may havea substituent(s)” represented by ring D refers to “5- to 10-memberednitrogen-containing heterocyclic group” of the above-described “3- to15-membered nitrogen-containing heterocyclic group” represented by ringD. Examples of pyrrolidine, piperidine, piperazine, azepane, or tropane,etc. are included.

The “substituents” in the “5- to 10-membered nitrogen-containingheterocyclic group which may have a substituent(s)” represented by ringD have the same meanings as the “substituents” in the “hydrocarbon groupwhich may have a substituent(s)” or “3- to 15-membered heterocyclicgroup which may have a substituent(s)” represented by R^(1A), R^(1B),R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) andR^(1L). The 1 to 10 substituents may exist wherever possible. When thenumber of substituents is two or more, each substituent may be same ordifferent.

The “hydroxy group which may be protected” represented by R² is the“hydroxy group” which may be protected by a “protecting group”. The“protecting group” of hydroxy group includes, for example, (1) C1-6alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,etc.) which may have 1 to 4 of substituents selected from (a) halogenatom such as chlorine, bromine or fluorine etc.; (b) C6-10 aryl such asphenyl or naphthyl etc.; (c) C7-12 aralkyl group such as benzyl orphenylethyl etc.; and (d) nitro group etc., (2) C6-10 aryl (e.g., phenylor naphthyl etc.) which may have 1 to 4 of substituents selected from(a) halogen atom such as chlorine, bromine or fluorine etc.; (b) C1-6alkyl group such as methyl, ethyl or propyl etc.; (c) C6-10 aryl such asphenyl or naphthyl etc.; (d) C7-12 aralkyl group such as benzyl orphenylethyl etc.; and (e) nitro group etc., (3) C7-12 aralkyl group(e.g., benzyl, phenylethyl or naphthylmethyl etc.) which may have 1 to 4of substituents selected from (a) halogen atom such as chlorine, bromineor fluorine etc.; (b) C1-6 alkyl group such as methyl, ethyl or propyletc.; (c) C6-10 aryl such as phenyl or naphthyl etc.; (d) C7-12 aralkylgroup such as benzyl or phenylethyl etc.; and (e) nitro group etc., (4)formyl, (5) C1-6 alkyl-carbonyl group (e.g., acetyl or propionyl etc.)which may have 1 to 4 of substituents selected from (a) halogen atomsuch as chlorine, bromine or fluorine etc.; (b) C1-6 alkyl group such asmethyl, ethyl or propyl etc.; (c) C6-10 aryl such as phenyl or naphthyletc.; (d) C7-12 aralkyl group such as benzyl or phenylethyl etc.; and(e) nitro group etc., (6) C6-10 aryl-oxycarbonyl group (e.g.,phenyloxycarbonyl or naphthyloxycarbonyl etc.) which may have 1 to 4 ofsubstituents selected from (a) halogen atom such as chlorine, bromine orfluorine etc.; (b) C1-6 alkyl group such as methyl, ethyl or propyletc.; (c) C6-10 aryl such as phenyl or naphthyl etc.; (d) C7-12 aralkylgroup such as benzyl or phenylethyl etc.; and (e) nitro group etc., (7)C6-10 aryl-carbonyl group (e.g., benzoyl or naphthylcarbonyl etc.) whichmay have 1 to 4 of substituents selected from (a) halogen atom such aschlorine, bromine or fluorine etc.; (b) C1-6 alkyl group such as methyl,ethyl or propyl etc.; (c) C6-10 aryl such as phenyl or naphthyl etc.;(d) C7-12 aralkyl group such as benzyl or phenylethyl etc.; and (e)nitro group etc., (8) C7-12 aralkyl-carbonyl group (e.g., benzylcarbonylor phenethylcarbonyl etc.) which may have 1 to 4 of substituentsselected from (a) halogen atom such as chlorine, bromine or fluorineetc.; (b) C1-6 alkyl group such as methyl, ethyl or propyl etc.; (c)C6-10 aryl such as phenyl or naphthyl etc.; (d) C7-12 aralkyl group suchas benzyl or phenylethyl etc.; and (e) nitro group etc., (9) pyranyl orfuranyl which may have 1 to 4 of substituents selected from (a) halogenatom such as chlorine, bromine or fluorine etc.; (b) C1-6 alkyl groupsuch as methyl, ethyl or n-propyl etc.; (c) C6-10 aryl such as phenyl ornaphthyl etc.; (d) C7-12 aralkyl group such as benzyl or phenylethyletc.; and (e) nitro group etc., or (10) tri-C1-4 alkylsilyl such astrimethylsilyl or triethylsilyl etc.

The “substituents” in the “amino group which may have a substituent(s)”represented by R² includes hydrocarbon group which may have asubstituent(s), —SO₂R²⁰¹ or ═NR²⁰² (wherein R²⁰¹ and R²⁰² is hydrocarbongroup which may have a substituent(s)). The “hydrocarbon group which mayhave a substituent(s)” has the same meaning as the “hydrocarbon groupwhich may have a substituent(s)” represented by R^(1A), R^(1B), R^(1C),R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K), and R^(1L). The1 or 2 substituents which amino group has may exist wherever possible.When the number of substituents is two or more, each substituent may besame or different. “Amino group which may have a substituent(s)”represented by R² is

(wherein the arrow represents a binding position to ring D, and R⁵¹,R⁵², R⁵³ and R⁵⁴ are each independently hydrogen atom, hydrocarbon groupwhich may have a substituent(s), 3- to 15-membered heterocyclic groupwhich may have a substituent(s), C1-4 alkoxy group which may have asubstituent(s), phenoxy which may have a substituent(s) or benzyloxywhich may have a substituent(s)). The “hydrocarbon group which may havea substituent(s)” and “3- to 15-membered heterocyclic group which mayhave a substituent(s)” have the same meanings as the “hydrocarbon groupwhich may have a substituent(s)” and “3- to 15-membered heterocyclicgroup which may have a substituent(s)” represented by R^(1A), R^(1B),R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) andR^(1L) respectively. “C1-4 alkoxy group” in the “C1-4 alkoxy group whichmay have a substituent(s)” includes, for example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy etc.The “substituents” of “C1-4 alkoxy group which may have asubstituent(s)”, “phenoxy group which may have a substituent(s)” and“benzyloxy group which may have a substituent(s)” include, for example,the “substituents” in the “hydrocarbon group which may have asubstituent(s)” represented by R^(1A), R^(1B), R^(1C), R^(1D), R^(1E),R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) and R^(1L), etc.

The “hydrocarbon group which may have a substituent(s)” represented byR² have the same meanings as the “hydrocarbon group which may have asubstituent(s)” represented by R^(1A), R^(1B), R^(1C), R^(1D), R^(1E),R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) and R^(1L). The 1 to 10substituents which the hydrocarbon group has may exist whereverpossible. When the number of substituents is two or more, eachsubstituent may be same or different. The “hydrocarbon group which mayhave a substituent(s)” represented by R² is

(wherein the arrow represents a binding position to ring D, and R⁵² andR⁵³ have the same meanings as described above.)

The “3- to 15-membered heterocyclic group which may have asubstituent(s)” represented by R² has the same meanings as the “3- to15-membered heterocyclic group which may have a substituent(s)”represented by R^(1A), R^(1B), R^(1C), R^(1D), R^(1E), R^(1F), R^(1G),R^(1H), R^(1J), R^(1K) and R^(1L).

C1-4 alkyl represented by R⁶ includes, for example, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

The “hydrocarbon group which may have a substituent(s)” represented byR⁵¹ have the same meanings as the “hydrocarbon group which may have asubstituent(s)” represented by R^(1A), R^(1B), R^(1C), R^(1D), R^(1E),R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) and R^(1L).

The “C1-15 alkyl” represented by R⁵¹ have the same meanings as the“C1-15 alkyl” as the “hydrocarbon group” in the “hydrocarbon group whichmay have a substituent(s)” represented by R^(1A), R^(1B), R^(1C),R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) and R^(1L).

The “aromatic ring group” in the “aromatic ring group which may have asubstituent(s)” represented by R⁵¹ refers to the “mono-, bi- ortricyclic carbocyclic group or heterocyclic group which havearomaticity” of the “hydrocarbon group” in the “hydrocarbon group whichmay have a substituent(s)” and “3- to 15-membered heterocyclic group” inthe “3- to 15-membered heterocyclic group which may have asubstituent(s)” represented by R⁵¹. The “mono-, bi- or tricycliccarbocyclic group which have aromaticity” include, for example, benzene,azulene, naphthalene, phenanthrene, anthracene ring, etc. The “mono-,bi- or tricyclic heterocyclic group which have aromaticity” include, forexample, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, thiadiazole, indole,isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene,indazole, quinoline, isoquinoline, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, benzofurazan, benzothiadiazole,benzotriazole, carbazole, beta-carboline, acridine, phenazine,dibenzofuran, dibenzothiophene, phenanthridine, phenanthroline,perimidine ring, etc.

The “substituents” in the “aromatic ring group which may have asubstituent(s)” represented by R⁵¹ have the same meanings as the“substituents” in the “hydrocarbon group which may have asubstituent(s)” or “3- to 15-membered heterocyclic group which may havea substituent(s)” represented by R^(1A), R^(1B), R^(1C), R^(1D), R^(1E),R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) and R^(1L). The 1 to 10substituents may exist wherever possible. When the number ofsubstituents is two or more, each substituent may be same or different.

The “mono-carbocyclic group or mono-heterocyclic group which havearomaticity” represented by R⁵¹ refers to monocyclic group of theabove-described “aromatic ring group” represented by R⁵¹. Examples ofbenzene, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole or thiadiazole ring etc. are included.

The “aromatic ring group which may have a substituent(s)” represented byR⁵⁶ have the same meanings as the above-described “aromatic ring groupwhich may have a substituent(s)” represented by R⁵¹.

Unless otherwise specifically mentioned, all isomers are included in thepresent invention. For example, alkyl, alkenyl, Alkynyl, alkoxy,alkylthio, alkylene, alkenylene and alkynylene include straight chainand branched ones. Moreover, all of isomers due to double bond, ring andfused ring (E-, Z-, cis- and trans-forms), isomers due to presence ofasymmetric carbon(s) etc. (R-, S-, α- and β-configuration, enantiomerand diastereomer), optically active substances having optical rotation(D-, L-, d- and l-forms), polar compound by chromatographic separation(more polar compound and less polar compound), equilibrium compounds,rotational isomers, a mixture thereof in any proportion and a racemicmixture are included in the present invention.

According to the present invention, symbol

represents β-configuration and symbol

represents α-configuration, β-configuration or the mixture of them.There is no particular limitation for the ratio of α-configuration andβ-configuration in the mixture.

Salts:

The salt of the compound of formula (I) includes all of the salt whichare non-toxic salts or pharmaceutically acceptable salts. With regard tothe pharmaceutically acceptable salts, those which are low-toxic andsoluble in water are preferred. Examples of appropriate salts of thecompound of formula (I) are salt with alkaline metal (such as potassium,sodium and lithium), salt with alkaline earth metal (such as calcium andmagnesium), ammonium salt (such as tetramethylammonium salt andtetrabutylammonium salt), salt with organic amine (such astriethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine andN-methyl-D-glucamine) and acid addition salt [such as inorganic acidsalt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphateand nitrate) and organic acid salt (e.g., acetate, trifluoroacetate,lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate,methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate,isothionate, glucuronate and gluconate), etc.]. The salt of the compoundof the present invention also includes solvates and also solvates withthe above-mentioned alkaline (earth) metal salt, ammonium salt, organicamine salt and acid addition salt. The solvate is preferably low-toxicand water-soluble. Examples of an appropriate solvate are solvates withwater and with alcoholic solvent (such as ethanol). The compounds of thepresent invention are converted to low-toxic salts or pharmaceuticallyacceptable salts by known methods.

Moreover, the salt includes a quaternary ammonium salt. The quaternaryammonium salt of the compound represented by formula (I) is the compoundwhere nitrogen of the compounds represented by formula (I) isquarternalized by R⁰ (R⁰ is C1-8 alkyl or C1-8 alkyl substituted byphenyl).

The salt also includes an N-oxide. The compound of the present inventioncan be converted into an N-oxide by known methods. The N-oxide is thecompound where nitrogen of the compound represented by formula (I) isoxidized.

Prodrugs:

A prodrug of the compound of formula (I) means a compound which isconverted to the compound of formula (I) by reaction with an enzyme,gastric acid or the like in the living body. For example, with regard toa prodrug of the compound of formula (I), when the compound of formula(I) has an amino group, compounds in which the amino group is, forexample, acylated, alkylated or phosphorylated (e.g., compounds in whichthe amino group of the compound of formula (I) is eicosanoylated,alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated, etc.); when the compound of formula(I) has a hydroxyl group, compounds where the hydroxyl group is, forexample, acylated, alkylated, phosphorylated or borated (e.g., compoundsin which the hydroxyl group of the compound of formula (I) isacetylated, palmitoylated, propanoylated, pivaloylated, succinylated,fumarylated, alanylated or dimethylaminomethylcarbonylated); and thatthe carboxyl group of the compound of formula (I) is, for example,esterified or amidated (e.g., compounds in which the carboxyl group ofthe compound of formula (I) is made into ethyl ester, phenyl ester,phenylethyl ester, carboxymethyl ester, dimethylaminomethyl ester,pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methylamide). Those compounds may beproduced by a known method per se. The prodrug of the compound offormula (I) may be either a hydrate or a non-hydrate. A prodrug of thecompound of formula (I) may also be a compound which is converted to thecompound of formula (I) under physiologic condition as described in“Iyakuhin no kaihatsu, Vol. 7 (Bunshi-sekkei), pp. 163-198(Hirokawa-Shoten), 1990”. And the compound of formula (I) may also belabeled by a radio isotope (such as ³H, ¹⁴C, ³⁵S, ¹²⁵I, etc,).

All definition represented by R¹, X, Y, ring A, ring B, ring D, and R²in the formula (I) in the present invention is preferred. All symbols ineach preferred group listed below have the same meanings as describedabove.

Preferred as R¹ is, for example, —N(R^(1A))SO₂—R^(1B),—SO₂NR^(1C)R^(1D), —S(O)_(m)R^(1G), —CONR^(1H)R^(1J), —NR^(1K)COR^(1L),etc., and more preferred is, for example, —N(R^(1A))SO₂—R^(1B),—SO₂NR^(1C)R^(1D), —S(O)_(m)R^(1G), —CONR^(1H)R^(1J), etc. Preferred asR^(1A), R^(1B), R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J),R^(1K) and R^(1L) is, for example, hydrogen atom or hydrocarbon groupwhich may have a substituent(s), etc. Most preferred as R¹ is, forexample, —NHSO₂CH₃, —NHSO₂CH₂CH₃, —SO₂NHCH₃, —SO₂CH₃, —CONHCH₂CH₂OCH₃,etc.

Preferred as X is, for example, a bond, —CR⁷R⁸—, —NR⁹—, —CO—, —O—, —S—,—SO—, —SO₂—, or —C(═N—OR¹⁰)—, etc. More preferably, X is bond, —O—, or—CH₂—, etc.

Preferred as Y is, for example, methylene, ethylene or propylene etc.More preferably, Y is methylene, ethylene. Most preferably, Y ismethylene.

Preferably, ring A or ring B is, for example, a “5- to 10-memberedcarbocyclic group or heterocyclic group” (it refers to 5- to 10-memberedcarbocyclic group or heterocyclic group of the above-described 3- to15-membered carbocyclic or heterocyclic group) etc. More preferably is,for example, a “5- to 10-membered unsaturated carbocyclic group orheterocyclic group” (it refers to 5- to 10-membered unsaturatedcarbocyclic group or heterocyclic group of the above-described 3- to15-membered carbocyclic or heterocyclic group) etc. More preferred is,for example, 5- or 6-aromatic ring such as benzene, pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, triazine, furan, thiophene, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole or thiadiazole ring etc. Most preferredis, for example, benzene or pyridine ring etc. Preferably, thesubstituent of ring A or ring B is, for example, hydrocarbon group,alkoxy, halogen atom, carboxy, alkanoylamide, etc., and more preferredis, for example, hydrocarbon group, alkoxy, halogen atom, etc., and mostpreferred is, for example, chloro atom, methyl, or methoxy, etc.

Preferably, ring D is, for example, a “5- to 10-memberednitrogen-containing heterocyclic group” (it refers to 5- to 10-memberednitrogen-containing heterocyclic group of the above-described 3- to15-membered nitrogen-containing heterocyclic group) etc., and morepreferred is, for example, tropane, pyrrolidine, piperidine, azepane, orpiperazine ring, etc., and most preferred is, for example, piperidinering. Preferably, ring D has no substituent or is substituted byhydrocarbon group, mono-C1-4 alkylamino group or di-C1-4 alkylaminogroup etc. More preferably, ring D has no substituent.

Preferred as R² is, for example, hydrocarbon group which may have asubstituent(s) or amino group which may have a substituent(s), etc.Preferred as the “substituents” is the “hydrocarbon group which may havea substituent(s)”. Concretely, more preferred as R², for example,

(wherein the arrow represents a binding position to ring D, each R⁵¹,R⁵², R⁵³ and R⁵⁴ has the same meanings as described above), etc.,independently. Preferably, R⁵¹, R⁵², R⁵³ or R⁵⁴ is, for example,hydrogen atom, hydrocarbon group which may have a substituent(s) or 3-to 15-membered heterocyclic group which may have a substituent(s) etc.Moreover, the compound wherein either among R⁵² and R⁵³ is hydrogen atomis preferred. More preferred as R² is, for example,

(R⁵⁵ has the same meaning as the “substituents” in the “hydrocarbongroup which may have a substituent(s)” represented by R^(1A), R^(1B),R^(1C), R^(1D), R^(1E), R^(1F), R^(1G), R^(1H), R^(1J), R^(1K) andR^(1L); n is 0 to 5, and other symbols have the same meanings asdescribed above), etc. Preferred as R⁵¹ is, for example, hydrocarbongroup which may have a substituent(s), etc., and more preferred is, forexample, C1-15 alkyl which may have a substituent(s), C6-14 aryl whichmay have a substituent(s), or R⁵⁶, etc., and most preferred is, forexample, butyl or phenyl which may have a substituent(s), etc. Preferredas the substituent is methyl, methoxy, trifluoromethyl, fluorine atom,etc., and more preferred is methyl or fluorine atom. Preferred as R⁵⁵is, for example, halogen atom, carbamoyl, or aminocarbonyl substitutedby C1-8 hydrocarbon group, etc., and more preferred is, for example,fluorine atom, chlorine atom, carbamoyl, N-methylaminocarbonyl, etc.Preferred as n is 1 to 3.

Preferred as R⁵⁶ is mono-carbocyclic group or mono-heterocyclic groupwhich have aromaticity which may have a substituent(s), and morepreferred is benzene, pyrrole, imidazole, triazole, tetrazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole or thiadiazole ring which mayhave a substituent(s), and most preferred is benzene ring which may havea substituent(s). Preferred as the substituent is methyl, methoxy,trifluoromethyl, fluorine atom, etc., and more preferred is methyl orfluorine atom.

In the present invention, the compound represented by formula (I)including the combination of the above-described preferable group andring is preferred.

For example, a compound wherein ring D is piperidine and Y is methylenegroup, i.e., a compound represented by formula (Ia)

(wherein all symbols have the same meanings as described above); acompound wherein ring D is piperidine and Y is methylene group, R² is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (Ib)

(wherein all symbols have the same meanings as described above); acompound wherein X is —O—, Y is methylene group, ring A and ring B areeach independently benzene which may have a substituent(s), ring D ispiperidine, R² is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (Ic)

(wherein ring A^(1a) and ring B^(1a) are each independently benzenewhich may have a substituent(s) and other symbols have the same meaningsas described above); a compound wherein X is —O—, Y is methylene group,ring A and ring B are each independently benzene which may have asubstituent(s), ring D is piperidine, R² is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (Id)

(wherein all symbols have the same meanings as described above);a compound wherein ring D is tropane ring and Y is methylene group, R²is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (Ie)

(wherein all symbols have the same meanings as described above); acompound wherein ring D is pyrrolidine ring and Y is methylene group, R²is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (If)

(wherein all symbols have the same meanings as described above); acompound wherein ring D is piperidine and Y is methylene group, R² is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (Ig)

(wherein all symbols have the same meanings as described above); acompound wherein ring D is azepane ring and Y is methylene group, R² is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (Ih)

(wherein all symbols have the same meanings as described above), saltsthereof, N-oxides thereof, solvates thereof, and prodrugs thereof arepreferred.

Preferred are compounds described in Examples, salts thereof, N-oxidesthereof, solvates thereof, and prodrugs thereof. More preferred are

-   (1)    5-({[butyl(1-{4-[4-(methylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,-   (2)    5-[({butyl[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,-   (3)    5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,-   (4)    5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,-   (5)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,-   (6)    5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2-chloro-4-fluorobenzamide,-   (7)    2-(5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorophenyl)acetamide,-   (8)    5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-methylbenzamide,-   (9)    5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,-   (10)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (11)    5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,-   (12)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (13)    N-[4-({5-[(4-{3-thienyl[(3-thienylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,-   (14)    2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (15)    N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]phenyl}methanesulfonamide,-   (16)    4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]-N-[2-(4-morpholinyl)ethyl]benzenesulfonamide,-   (17)    N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (18)    2-chloro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (19)    N-(4-{[5-({4-[({[4-chloro-3-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (20)    2-fluoro-5-{[((3-fluorophenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide,-   (21)    N-(3-fluorophenyl)-N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea,-   (22)    2-[4-({4-[[({4-fluoro-3-[(methylsulfonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,-   (23)    2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (24)    2-fluoro-N-methyl-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,-   (25)    2-[4-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,-   (26)    N′-(4-fluorophenyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]pyridin-3-yl}methyl)piperidin-4-yl]-N-phenylurea,-   (27)    N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (28)    N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide,-   (29)    N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,-   (30)    5-[({butyl[1-(4-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,-   (31)    N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,-   (32)    N-(4-{[5-({4-[{[(4-methylphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (33)    N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (34)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acetamide,

salts thereof, N-oxides thereof, solvates thereof, and prodrugs thereof,etc. Most preferred are

-   2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide,-   N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,-   5-[({butyl[1-(4-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,-   N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,-   N-(4-{[5-({4-[{[(4-methylphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acetamide,

salts thereof, N-oxides thereof, solvates thereof, and prodrugs thereof,etc.

In the present invention,

-   (1)    N-{4-[(5-{[4-((3-methylphenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,-   (2)    N-(2-fluoro-5-{[((3-methylphenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamide,-   (3)    N-(2-fluoro-5-{[((3-fluorophenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamide,-   (4)    N-(2-fluoro-5-{[((3-fluorophenyl){1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamide,-   (5)    N-[5-({[{1-[(6-{2-chloro-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-fluorophenyl)amino]carbonyl}amino)-2-fluorophenyl]acetamide,-   (6)    N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3-methylphenyl}methanesulfonamide,-   (7)    N-{3-chloro-4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,-   (8)    2-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-[(methylsulfonyl)amino]benzamide,-   (9)    2-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-N-methyl-5-[(methylsulfonyl)amino]benzamide,-   (10)    N-[4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-(methylsulfonyl)phenyl]methanesulfonamide,-   (11)    N-{2-[(5-{[4-((3-methylphenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-[(methylsulfonyl)amino]phenyl}acetamide,-   (12)    N-(4-{[5-({4-[[[(4-fluorophenyl)amino](imino)methyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (13)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonothioyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (14)    2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-azetidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (15)    N-(4-{[5-({(3R)-3-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (16)    N-[2-fluoro-5-({[{(3S)-1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-pyrrolidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide,-   (17)    N-(4-{[5-({(4R)-4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-azepanyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (18)    N-(4-{[5-({(4S)-4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-azepanyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (19)    2-fluoro-5-({[(1-{[6-({4-[(methylsulfonyl)amino]phenyl}sulfonyl)-3-pyridinyl]methyl}-4-piperidinyl)(phenyl)amino]carbonyl}amino)benzamide,-   (20)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]methyl}phenyl)methanesulfonamide,-   (21)    2-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(3-fluorophenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]benzamide,-   (22)    N-(3-methylphenyl)-N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea,-   (23)    N-[1-({6-[4-(ethylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-(3-fluorophenyl)-N′-(6-methyl-3-pyridinyl)urea,-   (24)    N-(3-fluorophenyl)-N-[1-({6-[4-(isopropylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N′-(6-methyl-3-pyridinyl)urea,-   (25)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]methyl}phenyl)ethanesulfonamide,-   (26)    2-fluoro-5-{[((3-fluorophenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-azetidinyl}amino)carbonyl]amino}benzamide,-   (27)    N-(4-{[5-({4-[{[(6-ethyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (28)    N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-6-methyl-2-pyridinyl)oxy]phenyl}methanesulfonamide,-   (29)    N-[2-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-(methylsulfonyl)phenyl]acetamide,-   (30)    N-(4-{[5-({4-[{[(6-ethyl-3-pyridinyl)amino]carbonyl}(3-fluorophenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (31)    N-{2-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(3-fluorophenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]phenyl}acetamide,-   (32)    N-{2-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)methyl]-5-[(methylsulfonyl)amino]phenyl}acetamide,-   (33)    N-[4-(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)phenyl]methanesulfonamide,-   (34)    2-fluoro-5-({[{1-[(2-methyl-6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (35)    N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)sulfonyl]phenyl}methanesulfonamide,-   (36)    N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(3-methylphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (37)    N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(3-methylphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (38)    2-fluoro-5-({[{1-[(2-methyl-6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-methylphenyl)amino]carbonyl}amino)benzamide,-   (39)    N-ethyl-2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (40)    2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonothioyl}amino)benzamide,-   (41)    2-fluoro-5-{[((3-fluorophenyl){(3S)-1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-pyrrolidinyl}amino)carbonyl]amino}-N-methylbenzamide,-   (42)    N-[5-({[{(4S)-1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-azepanyl}(phenyl)amino]carbonyl}amino)-2-fluorophenyl]acetamide,-   (43)    2-{[5-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(3-fluorophenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-N-methyl-5-[(methylsulfonyl)amino]benzamide,-   (44)    N-[5-({[{1-[(6-{2-chloro-4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-fluorophenyl)amino]carbonyl}amino)-2-fluorophenyl]acetamide,-   (45)    5-({[{(3R)-1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-pyrrolidinyl}(phenyl)amino]carbonyl}amino)-2-fluorobenzamide,-   (46)    N-(3-chloro-4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (47)    5-({[{1-[(6-{2-(aminocarbonyl)-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-fluorophenyl)amino]carbonyl}amino)-2-fluoro-N-methylbenzamide,-   (48)    2-fluoro-N-methyl-5-({[{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (49)    N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]sulfonyl}phenyl)methanesulfonamide,-   (50)    2-fluoro-N-methyl-5-{[((3-methylphenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide,-   (51)    2-fluoro-5-{[((3-methylphenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide,-   (52)    2-fluoro-5-{[((3-fluorophenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-N-methylbenzamide,-   (53)    N-(3-methyl-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (54)    N-(3-chloro-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (55)    N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)ethanesulfonamide,-   (56)    N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamide,-   (57)    N-(4-{[5-({(3S)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (58)    N-(4-{[5-({(4S)-4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-azepanyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,-   (59)    N-(4-{[5-({(3R)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pridinyl]oxy}phenyl)methanesulfonamide,-   (60)    2-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]benzamide,-   (61)    2-{[5-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(3-fluorophenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]benzamide,-   (62)    2-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]benzamide,-   (63)    N-[4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3-(methylsulfonyl)phenyl]methanesulfonamide,-   (64)    N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]methyl}phenyl)methanesulfonamide,-   (65)    N-{4-[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]phenyl}methanesulfonamide,-   (66)    N-{4-[(5-{[4-((3-methylphenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,-   (67)    N-[5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-fluorophenyl)amino]carbonyl}amino)-2-fluorophenyl]acetamide,-   (68)    2-fluoro-5-({[{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,-   (69)    5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)-2-fluorobenzamide,    and-   (70)    N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}ethanesulfonamide,    salts thereof, N-oxides thereof, solvates thereof, and prodrugs    thereof are also preferable.

Processes for the Preparation of the Compound of the Present Invention:

The compound of the present invention represented by formula (I) can beprepared by methods which properly improved and combined known methods,such as methods described below, methods described in Examples ormethods described in Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc, 1999). In each method described below, a startingmaterial can be used as a salt thereof. An example of the salt includesa salt of compound of formula (I) described above.

Among the compounds represented by formula (I), a compound wherein aspacer which is adjacent with ring D is —CH₂—, —CO— or —SO₂— can beprepared by alkylation, amidation or sulfonamidation by a compoundrepresented by formula (1)

(wherein Z is hydroxy group or a leaving group (e.g., halogen atom,p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group etc.), Y^(1P) is a bond or a spacer containing1 or 2 atoms as a main chain, Y^(2P) is —CH₂—, —CO— or —SO₂—, andR^(1P), X^(P), ring A^(P) and ring B^(P) have the same meanings as R¹,X, ring A and ring B respectively. With proviso that, carboxy group,hydroxy group, amino group or mercapto group in R^(1P), X^(P), Y^(1P),Y^(2P), ring A^(P) or ring B^(P) may be protected, if necessary. Othersymbols have the same meaning as described above) and a compoundrepresented by formula (2)

(wherein R^(2P) and ring D^(P) have the same meanings as R² and Drespectively. With proviso that, carboxy group, hydroxy group, aminogroup or mercapto group in R^(2P) or ring D^(P) may be protected, ifnecessary), if necessary, followed by removal of the protecting group.

The alkylation is well known. For example, it may be carried out in anorganic solvent (e.g., dimethylformamide, dimethylsulfoxide), in thepresence of alkaline (e.g., potassium carbonate, sodium carbonate,triethylamine, etc.), and in the presence or absence of sodium iodide orpotassium iodide at about 0 to 150° C.

The amidation is known. For example, it includes the method

(1) via an acyl halide,(2) via a mixed acid anhydride,(3) using a condensing agent.

These methods are explained as follows.

(1) The method via an acyl halide may be carried out, for example, byreacting carboxylic acid with an acyl halide (e.g., oxalyl chloride orthionyl chloride) in an organic solvent (e.g., chloroform,dichloromethane, diethyl ether or tetrahydrofuran) or without a solventat about −20° C. to reflux temperature. And then the obtained acylhalide derivative may be reacted with amine in an organic solvent (e.g.,chloroform, dichloromethane, diethyl ether or tetrahydrofuran) in thepresence of a base (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine or diisopropylethylamine etc.) at about 0 to 40°C. As an alternative, the obtained acyl halide derivative may be reactedwith amine in an organic solvent (e.g., dioxane, tetrahydrofuran) usingan alkaline aqueous solution (e.g., sodium hydrogen carbonate, sodiumhydroxide) at about −78 to 40° C.(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting carboxylic acid with an acyl halide (e.g., pivaloylchloride, p-toluenesulfonyl chloride or methanesulfonyl chloride) or anacid derivative (e.g., ethyl chloroformate or isobutyl chloroformate) inan organic solvent (e.g., chloroform, dichloromethane, diethyl ether,tetrahydrofuran) or without a solvent, in the presence of a base (e.g.,pyridine, triethylamine, dimethylaniline, dimethylaminopyridine ordiisopropylethylamine) at about 0 to 40° C. And then the obtained mixedacid anhydride derivative may be reacted with amine in an organicsolvent (e.g., chloroform, methylene chloride, diethyl ether ortetrahydrofuran), at about 0 to 40° C.(3) The method using a condensing agent may be carried out, for example,by reacting carboxylic acid with amine in an organic solvent (e.g.,chloroform, dichloromethane, dimethylformamide, diethyl ether ortetrahydrofuran) or without a solvent, in the presence or absence of abase (e.g., pyridine, triethylamine, dimethylaniline ordimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide(EDC), 1,1′-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,or 1-propanephosphonic acid cyclic anhydride (PPA)), in the presence orabsence of 1-hydroxybenzothiazole (HOBt), at about 0 to 40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g., argon, nitrogen) to avoid water in order to obtain apreferable result.

The sulfoneamidation is well known. For example, it may be carried outby reacting sulfonic acid with acyl halide (e.g., oxalyl chloride orthionyl chloride, phosphorus pentachloride or phosphorus trichloride) inan organic solvent (e.g., chloroform, dichloromethane, dichloroethane,diethyl ether, tetrahydrofuran or tert-butyl methyl ether) or without asolvent at about −20° C. to reflux temperature. And then the obtainedsulfonyl halide derivative may be reacted with amine in an organicsolvent (e.g., chloroform, dichloromethane, diethyl ether ortetrahydrofuran) in the presence of a base (e.g., diisopropylethylamine,pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.)at about 0 to 40° C.

The removal of the protecting group is known and may be carried out byfollowing method.

The carboxyl-protective group includes, for example, methyl, ethyl,allyl, tert-butyl, trichloro ethyl, benzyl (Bn) or phenacyl etc.

The protecting group of hydroxy includes, for example, methyl, trityl,methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM),2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES),tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl(Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl(Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc) etc.

The protecting group of amino includes such as benzyloxycarbonyl,tert-butoxycarbonyl, allyloxycarbonyl (Alloc),1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl,benzyloxymethyl (BOM) or 2-(trimethylsilyl)ethoxymethyl (SEM) etc.

The protective group of mercapto includes, for example, benzyl,methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP),diphenylmethyl and acetyl (Ac) etc.

With regard to the protective group for carboxyl, hydroxyl, amino andmercapto, there is no particular limitation to the above ones so far asit is a group which is able to be easily and selectively detached. Forexample, a deprotection reaction may be carried out by a methodmentioned in “T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons Inc, 1999”.

The reaction for removing the protective group for carboxyl, hydroxyl,amino or mercapto is known and its examples are as follows.

(1) a deprotection reaction by hydrolyzing reaction with an alkali;(2) a deprotection reaction under an acidic condition;(3) a deprotection reaction by hydrogenolysis;(4) a deprotection reaction of silyl;(5) a deprotection reaction using a metal; and(6) a deprotection reaction using metal complex.

Those methods will be specifically illustrated as follows.

(1) A deprotection reaction using an alkali is carried out, for example,at about 0 to 40° C. using a hydroxide of alkaline metal (such as sodiumhydroxide, potassium hydroxide and lithium hydroxide), a hydroxide ofalkaline earth metal (such as barium hydroxide and calcium hydroxide), acarbonate (such as sodium carbonate and potassium carbonate), an aqueoussolution thereof or a mixture thereof in an organic solvent (such asmethanol, tetrahydrofuran and dioxane etc.).(2) A deprotection reaction under an acidic condition is carried out,for example, at about 0 to 100° C. in an organic acid (e.g., aceticacid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonicacid), an inorganic acid (e.g., hydrochloric acid and sulfuric acid) ora mixture thereof (such as hydrogen bromide/acetic acid) in an organicsolvent (such as dichloromethane, chloroform, dioxane, ethyl acetate andanisole etc.).(3) A deprotection reaction by hydrogenolysis is carried out, forexample, at about 0 to 200° C. in a hydrogen atmosphere of ordinarypressure or high pressure or in the presence of ammonium formate in thepresence of a catalyst (such as palladium-carbon, palladium black;palladium hydroxide, platinum oxide and Raney nickel) in a solvent [suchas an ether type (such as tetrahydrofuran, dioxane, dimethoxyethane anddiethyl ether), an alcohol type (such as methanol and ethanol), abenzene type (such as benzene and toluene), a ketone type (such asacetone and methyl ethyl ketone), a nitrile type (such as acetonitrile),an amide type (such as dimethylformamide), water, ethyl acetate, aceticacid or a mixed solvent comprising two or more thereof].(4) A deprotection reaction of silyl is carried out, for example, atabout 0 to 40° C. using tetrabutylammonium fluoride in an organicsolvent miscible with water (such as tetrahydrofuran and acetonitrileetc.).(5) A deprotection reaction using metal is carried out, for example, atabout 0 to 40° C. with or without ultrasonic wave in the presence ofpowdery zinc in an acidic solvent (such as acetic acid, a buffer of pH4.2 to 7.2 and a mixed solution of a solution thereof with an organicsolvent such as tetrahydrofuran).(6) A deprotection reaction using a metal complex is carried out, forexample, at about 0 to 40° C. using a metal complex [such astetrakistriphenylphosphine palladium (0), bis(triphenylphosphine)palladium (II) dichloride, palladium (II) acetate andtris(triphenylphosphine) rhodium (I) chloride] in the presence orabsence of a phosphine agent (such as triphenyl phosphine) in thepresence of a trap reagent (such as tributyltin hydride, triethylsilane,dimedone, morpholine, diethylamine and pyrrolidine), an organic acid(such as acetic acid, formic acid and 2-ethylhexanoic acid) and/or anorganic acid salt (such as sodium 2-ethylhexanoate and potassium2-ethylhexanoate) in an organic solvent (such as dichloromethane,dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxaneand ethanol), water or a mixed solvent thereof.

Apart from the above, the deprotection may also be effected, forexample, according to the methods described in T. W. Greene, ProtectiveGroups in Organic Synthesis, Wiley, New York, 1999.

As persons skilled in the art can easily understand that the aimedcompound of the present invention is able to be easily produced by usingappropriate ones among those deprotection reactions.

Among the compounds of the present invention represented by formula (I),a compound wherein R² is amino group which may have a substituent(s),i.e., a compound represented by formula (I-a)

(wherein R²⁻¹ is amino group which may have a substituent(s) and othersymbols have the same meanings as described above) can be prepared byreductive amination of a compound represented by formula (3)

(wherein all symbols have the same meanings as described above) and acompound

(wherein R³⁰¹ and R³⁰², which are the same or different, are each ahydrogen atom or have the same meanings as the “substituents” of theabove-described “amino group which may have a substituent(s)”, and othersymbols have the same meanings as described above. With proviso that,carboxy group, hydroxy group, amino group or mercapto group in R³⁰¹ orR³⁰² may be protected, if necessary), if necessary, followed by removalof the protecting group.

The reductive amination is well known. For example, it may be carriedout with reducing agent (e.g., sodium triacetoxyborohydride or sodiumcyanoborohydride) at about 0 to 40° C. in an organic solvent (e.g.,dichloroethane, dichloromethane or dimethylformamide) in the presence orabsence of tertiary amine (e.g., triethylamine ordiisopropylethylamine), in the presence or absence of acetic acid.

The removal of the protecting group may be carried out by the abovedescribed method.

Among the compound of the present invention represented by formula (I),a compound wherein R² is

(wherein all symbols have the same meanings as described above), i.e., acompound represented by formula (I-d)

(wherein all symbols have the same meanings as described above) can beprepared by a below reaction using a compound represented by formula (5)

(wherein R^(51P) has the same meaning as R⁵¹ and other symbols have thesame meanings as described above. With proviso that, carboxy group,hydroxy group, amino group or mercapto group in R^(51P) may beprotected, if necessary) and a compound represented by (6)

R^(52P)—COOH  (6)

(wherein R^(52P) has the same meaning as R⁵² and other symbols have thesame meanings as described above. With proviso that, carboxy group,hydroxy group, amino group or mercapto group in R^(52P) may beprotected, if necessary), if necessary, followed by removal of theprotecting group.

The reaction is well known. For example, it may be carried out in anorganic solvent (e.g., N,N-dimethylformamide, toluene ortetrahydrofuran) with base (e.g., pyridine, triethylamine,dimethylaniline, dimethylaminopyridine or diisopropylethylamine) atabout 20 to 120° C.

The removal of the protecting group may be carried out by the abovedescribed method.

Moreover, the compound represented by formula (I-d) can be prepared by aurea-forming reaction using the compound represented by formula (5) anda compound represented by formula (7)

R^(52P)—NH₂  (7)

(wherein the symbol has the same meaning as described above), ifnecessary, followed by removal of the protecting group.

The reaction is well known. For example, it may be carried out in anorganic solvent (e.g., tetrahydrofuran or N,N-dimethylformamiden) in thepresence of triphosgene with base (e.g., triethylamine) at about 0 to40° C. Moreover, it may be carried out in an organic solvent (e.g.,dichloromethane or N,N-dimethylformamiden) in the presence of1,1′-carbonylbis-1H-imidazole (CDI) with base (e.g., triethylamine orN-methylmorpholine) or without base at about 0 to 80° C.

The removal of the protecting group may be carried out by the abovedescribed method.

Among a compound of the present invention represented by formula (I), acompound wherein Y is methylene, i.e., a compound represented by formula(I-e)

(wherein all symbols have the same meanings as described above) can beprepared by reductive amination of a compound represented by formula (8)

(wherein all symbols have the same meanings as described above) and thecompound represented by formula (2), if necessary, followed by removalof the protecting group.

The reductive amination and the removal of the protecting group may becarried out by the above described method.

Among the compounds represented by formula (I), a compound wherein atleast one nitrogen atom is quaternary ammonium salt, i.e., a compoundsof formula (I-2)

(wherein R¹⁻², R²⁻², X², Y², ring A², ring B² and ring D² have the samemeanings as R¹, R², X, Y, ring A, ring B and ring D respectively, and N²is nitrogen atom. With the proviso that, at least one nitrogen atom isquaternary ammonium salt, and Q⁻ is a halogen ion) can be prepared byreacting the compound of formula (I) with the compounds of formula (9)

R⁰-Q  (9)

(wherein R^(o) is C1-8 alkyl or C1-8 alkyl substituted by phenyl, and Qis halogen).

The reaction is well known, and it may be carried out, for example, inan organic solvent (acetone, dimethylformamide or methyl ethyl ketoneetc.) at about 0 to 40° C.

Among the compounds of formula (I), a compound where at least onenitrogen is N-oxide, i.e., a compound of formula (I-3)

(wherein R¹⁻³, R²⁻³, X³, Y³, ring A³, ring B³ and ring D³ have the samemeanings as R¹, R², X, Y, ring A, ring B and ring D respectively and N³is nitrogen atom. With the proviso that, at least one nitrogen atomrepresents N-oxide) can be prepared by an oxidation of a compound offormula (I).

The oxidation is well known and it may be carried out, for example, in asuitable organic solvent (e.g., dichloromethane, chloroform, benzene,hexane or tert-butylalcohol) in the presence of an excessive oxidizingreagent (hydrogen peroxide, sodium periodate, acyl nitrite, sodiumperborate, peroxidized acid (for example, 3-chloroperbenzoic acid orperacetic acid etc.), OXONE (brand name, OXONE is an abbreviation forpotassium peroxymonosulfate), potassium permanganate or chromic acidetc.) at about 20 to 60° C.

The compound of the present invention can be prepared by these reactionsor reactions modified a part of them.

Other starting compounds or compounds used as reagent are knowncompounds can be prepared easily by combination of known methods, forexample the methods described in Comprehensive Organic Transformations:A Guide to Functional Group Preparations, 2nd Edition (Richard C.Larock, John Wiley & Sons Inc, 1999) or Elmer J. Rauckman et al., J.Org. Chem., vol. 41, No. 3, 1976, p 564-565 etc.

In each reaction of the specification, the reactions with heating, aswill be apparent to those skilled in the art, it may be carried withwater bath, oil bath, sand bath and microwave.

In each reaction of the specification, it may be used a solid phasereagent which is supported by polymer (for example, polystyrene,polyacrylamide, polypropylene or polyethyleneglycol etc.).

In each reaction of the specification, the obtained products may bepurified by conventional techniques. For example, the purification maybe carried out by distillation at atmospheric or reduced pressure, byhigh performance liquid chromatography with silica gel or magnesiumsilicate, by thin layer chromatography, by ion-exchange resin, byscavenger resin, by column chromatography, by washing or byrecrystallization. The purification may be done each reaction or afterseveral reactions.

In a reaction using polystyrene resin of the specification, the obtainedproducts may be purified by conventional techniques. For example, thepurification may be carried out by rinsing them with a solvent(dimethylformamide, dichloromethane, methanol, tetrahydrofuran, toluene,acetic acid/toluene, etc.) more than once.

Toxicity:

The toxicity of the compound represented by formula (I), the saltthereof, the N-oxide thereof or the solvate thereof, or the prodrugthereof (hereinafter referred to as “the compound of the presentinvention”) is very low and therefore it may be considered safe forpharmaceutical use.

Application to Pharmaceuticals:

The compound of the present invention has good solubility andabsorbability. And the compound of the present invention has a weekinhibitory activity against drug-metabolizing enzyme. These nature arethe physical, chemical, and pharmaceutical property required to drugs,and the compound of the present invention have the proper conditions toan excellent drug [Ref. (The Merck Manual of Diagnosis and Therapy(17^(th) Ed), Merck & Co.)].

It can be assessed that the compound of the present invention is usefulas a drug by various experimental methods described below, methodsdescribed in Biological Examples, and their methods which properlyimproved. It can be also easily assessed that the compound of thepresent invention has a good pharmacokinetic property such as a lengthof serum half-life, a stability in the gastrointestinal tract, anabsorption of oral preparations, bioavailability, etc. by known methods,for example, a method described in “Yakubutsu bioavailability (Hyouka tokaizen no kagaku), Jul. 6, 1998, Gendaiiryou-sha”, etc.

(I) Evaluation Experiment of an Inhibitory Activity AgainstDrug-Metabolizing Enzymes of the Compound of the Present Invention (i)Inhibitory Activity Against Human CYP2C9

Inhibitory activity against human CYP2C9 of the compound of the presentinvention can be evaluated by a method of Sato et al. (Yakubutsudotai(Xenobio. Metabol. and Dispos.), 16 (2), 115-126 (2001)), which isimproved in assaying accuracy and/or assaying sensitivity.

(ii) Inhibitory Activity Against Human CYP3A4

Inhibitory activity against human CYP3A4 of the compound of the presentinvention can be evaluated by an improved method described in DrugMetabolism and Disposition, Vol. 28(12), 1440-1448 (2000).

For example, a reaction solution consisted of potassium phosphate buffer(pH7.4) (final concentration: 200 mM), magnesium chloride hexahydrate(final concentration: 5 mM), substrate (7-benzyloxyquinoline (7-BQ),final concentration: 40 μM), and expression system microsome(Daiichikagakuyakuhin, final concentration: 0.25 mg/mL) is prepared. 100μL of the reaction solution is dispensed in 96-well plate, and added by50 μL of an aqueous solution containing test a compound and 0.8%acetonitrile, to carry out 10 minutes of preincubation at 37° C. 50 μLof a reduced nicotinamide adenine dinucleotide phospate (NADPH, 4 mM) isadded to initiate a reaction. The fluorescence intensity of each well ismeasured at the time when NADPH is added and after incubated for 30minutes. Excitation wavelength at 409 nm and emission wavelength at 530nm of quinolinol, which is metabolite of substrate, is measured.Inhibition ratio (%) of the test compound is calculated by the followingcalculation formula to obtain IC₅₀ value.

Inhibition ratio(%)=[1−{(measured value when a test compound isadded)−(blank value)/(control value-blank value)}]×100

(II) Evaluation Experiment of a Toxicity of the Compound of the PresentInvention (i) Single Acute Toxicity Test in Rat

The test compound is administered to six-week Crj:CD (SD) rat by singleintravenous dose or single oral administration. Toxicity can beevaluated by contrast with value at no addition of the test compound.Basic evaluation of toxicity can be done by, for example, observation ofperformance status or locomotor activity, etc.

(ii) Evaluation of the Activity of the Compound of the Present InventionAgainst hERG I_(Kr) Current

According to the report by Zou et al. (Biophys. J., Vol. 74, 230-241(1998)), using HEK293 cell overexpressed of human ether-a-go-go-relatedgene (hERG), max tale current of hERG I_(Kr) current induced bydepolarization pulse followed by repolarization pulse is measured bypatch-clamp recording. Rate of change (inhibition rate) is calculated bycomparison max tale current between before addition of the test compoundand 10 minutes after. The influence of the test compound against hERGI_(Kr) current can be evaluated by the inhibition rate

The compounds of the present invention has the antagonistic activityagainst chemokine receptor, especially CCR5 in animal included human,especially human, so they are useful in preventing and/or treatingCCR5-related diseases, for example, various inflammatory diseases(asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoidarthritis, rhinitis, conjunctivitis, inflammatory bowel disease such asulcerative colitis, etc.), immunological diseases (autoimmune diseases,rejection in organ transplantation (rejection of graft of solid organ,rejection of graft of pancreatic islet cells in therapy for diabetes,GVHD (graft-versus-host disease), etc.), immunosuppression, psoriasis,multiple sclerosis, etc.), infectious diseases (infection with humanimmunodeficiency virus, acquired immunodeficiency syndrome, infectionwith RSV, etc.), allergic diseases (atopic dermatitis, urticaria,allergic bronchoplumonary aspergillosis, allergic eosinophilicgastroenteritis, etc.), cardiovascular diseases (arteriosclerosis,ischemic reperfusion injury, etc.), acute respiratory distress syndrome,shock accompanying bacterial infection, diabetes, cancer metastasis andso on.

The compounds of the present invention has the inhibitory activityagainst cell migration in animal included human, especially human, sothey are useful in preventing and/or treating various inflammatorydiseases (asthma, nephritis, nephropathy, hepatitis, arthritis,rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory boweldisease such as ulcerative colitis, etc.), immunological diseases(autoimmune diseases, rejection in organ transplantation (rejection ofgraft of solid organ, rejection of graft of pancreatic islet cells intherapy for diabetes, GVHD, etc.), immunosuppression, psoriasis,multiple sclerosis, etc.), infectious diseases (infection with humanimmunodeficiency virus, acquired immunodeficiency syndrome, infectionwith RSV, etc.), allergic diseases (atopic dermatitis, urticaria,allergic bronchoplumonary aspergillosis, allergic eosinophilicgastroenteritis, etc.), cardiovascular diseases (arteriosclerosis,ischemic reperfusion injury, etc.), acute respiratory distress syndrome,shock accompanying bacterial infection, diabetes, cancer metastasis andso on.

For the purpose above described, the compounds of the present inventionmay be normally administered systemically or locally, usually by oral orparenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 mg to 1000 mg, by oraladministration, up to several times per day, and from 1 mg to 100 mg, byparenteral administration (preferably intravenous administration), up toseveral times per day, or continuous administration from 1 to 24 hoursper day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered for example,in the form of solid for oral administration, liquid forms for oraladministration, injections, liniments or suppositories for parenteraladministration.

Solid forms for oral administration include compressed tablets, pills,capsules, dispersible powders, and granules. Capsules include hardcapsules and soft capsules.

In such solid forms, one or more of the active compound(s) may beadmixed with vehicles (such as lactose, mannitol, glucose,microcrystalline cellulose or starch), binders (such as hydroxypropylcellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate),disintegrants (such as cellulose calcium glycolate), lubricants (such asmagnesium stearate), stabilizing agents, and solution adjuvants (such asglutamic acid or aspartic acid) and prepared according to methods wellknown in normal pharmaceutical practice. The solid forms may, ifdesired, be coated with coating agents (such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), orbe coated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptablesolutions, suspensions, emulsions, syrups and elixirs. In such forms,one or more of the active compound(s) may be dissolved, suspended oremulsified into diluent(s) commonly used in the art (such as purifiedwater, ethanol or a mixture thereof). Besides such liquid forms may alsocomprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavoring agents, aroma,preservative or buffering agent.

Injections for parenteral administration include sterile aqueous,suspensions, emulsions and solid forms which are dissolved or suspendedinto solvent(s) for injection immediately before use. In injections, oneor more of the active compound(s) may be dissolved, suspended oremulsified into solvent(s). The solvents may include distilled water forinjection, saline, vegetable oil, propylene glycol, polyethylene glycol,alcohol such as ethanol, or a mixture thereof. Injections may comprisesome additives, such as stabilizing agents, solution adjuvants (such asglutamic acid, aspartic acid or POLYSORBATE80 (registered trade mark)),suspending agents, emulsifying agents, soothing agent, buffering agents,preservative. They may be sterilized at a final step, or may be preparedaccording to sterile methods. They may also be manufactured in the formof sterile solid forms such as freeze-dried products, which may bedissolved in sterile water or some other sterile diluent(s) forinjection immediately before use.

Other forms for parenteral administration include liquids for externaluse, ointments and endermic liniments, inhalations, sprays,suppositories and vaginal suppositories which comprise one or more ofthe active compound(s) and may be prepared by methods known per se.

Sprays may comprise additional substances other than diluents, usedcommonly, stabilizers such as sodium hydrogensulfite and buffers capableof imparting isotonicity, for example, isotonic buffers such as sodiumchloride, sodium citrate or citric acid.

The compounds of the present invention may be used together with otherdrugs, for example, preventive and/or treating agent(s) for HIVinfection (particularly agents for prevention and/or treatment forAIDS), or agent(s) for rejection in organ transplantation and/orautoimmune diseases. In that case, the drug as such may be mixed withpharmacologically acceptable excipient, binder, disintegrating agent,lubricant, stabilizer, solubilizer, diluent, etc. either separately orsimultaneously to make into a pharmaceutical preparation and that can beadministered either orally or parenterally as a pharmaceuticalcomposition for prevention and/or treatment of HIV infection rejectionin organ transplantation and/or autoimmune diseases.

The compounds of the present invention have an infection inhibitingactivity to HIV which acquired resistance to other agents for preventiveand/or treating HIV infection (particularly agents for prevention and/ortreatment for AIDS). Therefore, it is also able to be used forHIV-infected patients to whom other agents for preventive and/ortreating HIV infection are no longer effective. In that case, althoughthe compound of the present invention may be used solely, it may be alsoused together with agents for preventive and/or treating HIV infectionwhere infected HIV strain acquired resistance or with other drugs.

The present invention covers the combination of the compounds of thepresent invention with drugs which do not inhibit the REV infectionwhereby preventive and/or treating effect for HIV infection is enhancedas compared with a single preparation.

Examples of other agent for preventive and/or treating HIV infectionused for a combination with the compounds of the present invention arereverse transcriptase inhibitor, protease inhibitor, chemokineantagonist (such as CCR2 antagonist, CCR3 antagonist, CCR4 antagonist,CCR5 antagonist CXCR3 antagonist and CXCR4 antagonist), integraseinhibitor, fusion inhibitor, antibody to surface antigen of HIV andvaccine of HIV.

Reverse transcriptase inhibitors are concretely (1)nucleoside/nucleotide reverse transcriptase inhibitors: zidovudine(brand name: Retrovir), didanosine (brand name: Videx), zalcitabine(brand name: HIVID), stavudine (brand name: Zerit), lamivudine (brandname: Epivir), abacavir (brand name: Ziagen), adefovir, adefovirdipivoxil, emtricitabine (brand name: Coviracil) or PMPA (brand name:Tenofovir) etc. and (2) nonnucleoside reverse transcriptase inhibitors:nevirapine (brand name: Viramune), delavirdine (brand name: Rescriptor),efavirenz (brand name: Sustiva, Stocklin) or capravirine (AG1549) etc.

Protease inhibitors are concretely indinavir (brand name: Crixivan),ritonavir (brand name: Norvir), nelfinavir (brand name: Viracept),saquinavir (brand name: Invirase, Fortovase), amprenavir (brand name:Agenerase), lopinavir (brand name: Kaletra) or tipranavir etc.

As chemokine antagonists, internal ligand of chemokine receptor, itsderivatives, its non-peptide low molecular compound or antibody ofchemokine receptor are included.

The examples of internal ligand of chemokine receptor are concretely,MIP-1α, MTP-1β, RANTES, SDF-1α, SDF-1β, MCP-1, MCP-2, MCP-4, Eotaxin andMDC etc.

The derivatives of internal ligand are concretely, AOP-RANTES,Met-SDF-1α, Met-SDF-1β etc.

Antibodies of chemokine receptor are concretely, Pro-140 etc.

CCR2 antagonists are concretely written in specification of WO99/07351,WO99/40913, WO00/46195, WO00/46196, WO00/46197, WO00/46198, WO00/46199,WO00/69432 or WO00/69815 or in Bioorg. Med. Chem. Lett., 10, 1803 (2000)etc.

CCR3 antagonists are written in, for example, specification ofDE19837386, WO99/55324, WO99/55330, WO00/04003, WO00/27800, WO00/27835,WO00/27843, WO00/29377, WO00/31032, WO00/31033, WO00/34278, WO00/35449,WO00/35451, WO00/35452, WO00/35453, WO00/35454, WO00/35876, WO00/35877,WO00/41685, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/53172,WO00/53600, WO00/58305, WO00/59497, WO00/59498, WO00/59502, WO00/59503,WO00/62814, WO00/73327 or WO01/09088 etc.

CCR5 antagonists are, for example, TAK-779, SCH-351125 (SCH-C),SCH-417690 (SCH-D), UK-427857, GW873140 (ONO-4128), TAK-220 etc.Moreover, it includes compounds written in, for example, specificationof WO99/17773, WO99/32100, WO00/06085, WO00/06146, WO00/10965,WO00/06153, WO00/21916, WO00/37455, EP1013276, WO00/38680, WO00/39125,WO00/40239, WO00/42045, WO00/53175, WO00/42852, WO00/66551, WO00/66558,WO00/66559, WO00/66141, WO00/68203, JP2000309598, WO00/51607,WO00/51608, WO00/51609, WO00/51610, WO00/56729, WO00/59497, WO00/59498,WO00/59502, WO00/59503, WO00/76933, WO98/25605, WO99/04794, WO99/38514,Bioorg. Med. Chem. Lett., 11, 2663 (2003), Curr. Med. Chem.Anti-Infective Agents, 4, 133 (2005), Current Opinion in Pharmacology,4, 447 (2004), or Current Opinion in Investigational Drugs, 5, 851(2004), etc.

CXCR3 antagonists are written in, for example, specification ofWO01/16114, WO02/083143, WO02/085862, U.S. Pat. No. 6,469,002, orWO03/101970, etc.

CXCR4 antagonists are, for example, AMD-3100, AMD-070, T-22, KRH-1120,KRH-1636, KRH-2731 or the compounds written in specification ofWO00/66112 etc.

Integrase inhibitors are Equisetin, Temacrazine, PL-2500, V-165,NSC-618929, L-870810, L-708906 analog, S-1360, or 1838, etc.

Fusion inhibitors are concretely, T-20 (Pentafuside) and T-1249 etc.

The examples of combination agents written above are intended toillustrate the present invention, but do not limit them.

The typical examples of the usual the dosage level in clinical trials ofreverse transcriptase inhibitors or protease inhibitors written beloware intended to illustrate the present invention, but do not limit them.

-   Zidovudine: 100 mg capsule, 200 mg per dose, 3 times per day;    -   300 mg tablet, 300 mg per dose, twice per day;-   didanosine: 25-200 mg tablet, 125-200 mg per dose, twice per day;-   zalcitabine: 0.375-0.75 mg tablet, 0.75 mg per dose, 3 times per    day;-   stavudine: 15-40 mg capsule, 30-40 mg per dose, twice per day;-   lamivudine: 150 mg tablet, 150 mg per dose, twice per day;-   abacavir: 300 mg tablet, 300 mg per dose, twice per day;-   nevirapine: 200 mg tablet, 200 mg per dose, once per day for 14 days    and then twice per day;-   delavirdine: 100 mg tablet, 400 mg per dose, 3 times per day;-   efavirenz: 50-200 mg capsule, 600 mg per dose, once per day;-   indinavir: 200-400 mg capsule, 800 mg per dose, 3 times per day;-   ritonavir: 100 mg capsule, 600 mg per dose, twice per day;-   nelfinavir: 250 mg tablet, 750 mg per dose, 3 times per day;-   saquinavir: 200 mg capsule, 1,200 mg per dose, 3 times per day;-   amprenavir: 50-150 mg tablet, 1,200 mg per dose, twice per day.

Examples of other agent for preventive and/or treating rejection inorgan transplantation used for a combination with the compounds of thepresent invention are immunosuppressants.

Examples of the immunosuppressant include tacrolimus (FK506),cyclosporin, sirolimus (rapamycin), corticosteroids, azathioprine,mycophenolate mofetil, FTY-720, cyclophosphamide, or cell-surface ligandantibody, etc.

Examples of the cell-surface ligand antibody include Atgam,Thymoglobulin, Simulect, Zanapax, or Orthoclone, etc.

Examples of other agent for preventive and/or treating autoimmunediseases used for a combination with the compounds of the presentinvention are nonsteroidal antiinflammatory drug, disease modifyinganti-rheumatic drug (DMARDs, slow-acting anti-rheumatic drug), steroids,immunosuppressant agent, antiinflammatory enzyme preparations,chondroprotective agents, T-cell inhibitors, TNFα inhibitor (includeprotein preparation such as anti-TNFα antibody), prostaglandin synthaseinhibitor, IL-1 inhibitor, IL-6 inhibitor (include protein preparationsuch as anti-IL-6 receptor antibody), interferon gamma agonists,prostaglandins, phosphodiesterase inhibitor, metalloproteinaseinhibitor, etc.

Examples of the nonsteroidal antiinflammatory drug include sasapyrine,sodium salicylate, aspirin, aspirin dialuminate formulation, diflunisal,indomethacin, suprofen, ufenamate, dimethylisopropyl azulen, bufexamac,felbinac, diclofenac, tolmetin sodium, Clinoril, fenbufen, napmetone,proglumetacin, indomethacin farnesil, acemetacin, proglumetacin maleate,amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol,naproxen, flurbiprofen, flurbiprofen axethyl, ketoprofen, fenoprofencalcium, tiaprofenen, oxaprozin, pranoprofen, loxoprofen sodium,aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate,tolfenamic acid, floctafenine, ketophenylbutazone, oxyfenbutazone,piroxicam, tenoxicam, anpiroxicam, napageln cream, epirizole, tiaramidehydrochloride, tinoridine hydrochloride, emorfazone, sulpyrine,Migrenin, Saridon, Sedes G, Amipylo N, Sorbon, pyrine systemantipyretics, acetaminophen, phenacetin, dimethothiazine mesylate,simetride formulation, or antipyrine system antipyretics, etc.

Examples of the disease modifying anti-rheumatic drug (DMARDs,slow-acting anti-rheumatic drug) include, for example, gold thioglucose,aurothiomalate sodium, auranofin, actarit, D-penicillamine preparations,lobenzarit disodium, bucillamine, hydroxychloroquine,salazosulfapyridine, methotrexate, or leflunomide, etc.

Examples of the steroids for external application include clobetasolpropionate, diflorasone acetate, fluocinonide, monometasonefurancarboxylate, betamesone dipropionate, betamesone butyropropionate,betamesone valerate, difluprednate, budesonide, diflucortolone valerate,amcinonide, halcinonide, dexamethasone, dexamethasone propionate,dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone acetopropionate, deprodonepropionate, prednisolone valeroacetate, fluocinolone acetonide,beclometasone dipropionate, triamcinonide acetonide, flumethasonepivalate, prednisolone, beclometasone propionate, and fludroxycortide,etc.

Examples of the steroids for internal use or injection include cortisoneacetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisonesodium succinate, fludrocortisone acetate, prednisolone, prednisoloneacetate, prednisolone sodium succinate, prednisolone butylacetate,prednisolone sodium phosphate, halopredon acetate, methyl prednisolone,methyl prednisolone acetate, methyl prednisolone sodium succinate,triamicinolon, triamicinolon acetate, triamicinonolon acetonide,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,dexamethasone palmitate, paramethasone acetate, and betamethasone, etc.

Examples of the steroids as an inhalant includebeclomethasonepropionate, fluticasone propionate, budesonide,flunisolide, triamicinolon, ST-126P, ciclesonide, dexamethasonepalomitionate, monometasone furancarboxylate, prasterone sulfonate,deflazacort, methylprednisolone suleptanate, and methylprednisolonesodium succinate, etc.

Examples of the antiinflammatory enzyme preparations include, forexample, lysozyme chloride, bromelain, pronase, serrapeptase, orstreptokinase-streptodornase, etc.

Examples of the chondroprotective agents include, for example,hyaluronate sodium, glucosamine, chondroitin sulfate, andglucosaminoglycan polysulfate, etc.

Examples of TNFα inhibitor (include protein preparation such asanti-TNFα antibody) include, for example, infliximab, adalimumab, oretanercept, etc.

Examples of the prostaglandin synthase inhibitor include, for example,salazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid,JTE-522, auranofin, carprofen, diphenpyramid, flunoxaprofen,flurbiprofen, indomethacin, ketoprofen, lornoxicam, loxoprofen,Meloxicam, oxaprozin, parsalmide, piproxen, piroxicam, piroxicambetadex, piroxicam cinnamate, tropine indomethacinate, zaltoprofen, andpranoprofen, etc.

Examples of IL-1 inhibitor (include protein preparation such as humanIL-1 receptor antagonist) include, for example, anakinra, etc.

Examples of IL-6 inhibitor (include protein preparation such asanti-IL-6 receptor antibody) include, for example, MRA, etc.

Examples of the prostaglandins (hereinafter abbreviated as “PG”) includePG receptor agonist, and PG receptor antagonist, etc. Examples of the PGreceptor include PGE receptor (EP1, EP2, EP3, and EP4), PGD receptor(DP, CRTH2), PGF receptor (FP), PGI receptor (IP), or TX receptor (TP),etc.

Examples of the phosphodiesterase inhibitor include, for example,rolipram, cilomilast (trade name: Ariflo), Bay 19-8004, NIK-616,roflumilast (BY-217), cipamfylline (BGL-61063), atizolam (CP-80633),SCH-351591, YM-976, V-11294A, PD-168787, D-4396, IC-485, or ONO-6126 asPDE-4 inhibitor, etc.

Examples of other agent for preventive and/or treating other allergicdiseases, for example, asthma used for a combination with the compoundsof the present invention are steroids, β₂ adrenoreceptor stimulant,leukotriene receptor antagonist, thromboxane synthetase inhibitor,thromboxane A₂ receptor antagonist, mediator releasing inhibitor,antihistamines, xanthine derivatives, anticholinergic agent, cytokineinhibitor, prostaglandins, forskolin, phosphodiesterase inhibitor,elastase inhibitor, metalloproteinase inhibitor, expectorant, andantibiotic.

Examples of the β₂ adrenoreceptor stimulant include fenoterolhydrobromide, salbutamol sulfate, terbutaline sulfate, formoterolfumarate, salmeterol xinafoate, isoprotenol sulfate, orciprenalinsulfate, chloroprenalin sulfate, epinephrine, trimetoquinolhydrochloride, hexoprenalinmesyl sulfate, procaterol hydrochloride,tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride,clenbuterol hydrochloride, mabuterol hydrochloride, ritodrinehydrochloride, bambuterol, dopexamine hydrochloride, meradrin tartrate,AR-C68397, levosalbutamol, R,R-formoterol, KUR-1246, KUL-7211,AR-C89855, and S-1319, etc.

Examples of the leukotriene receptor antagonist include pranlukasthydrate, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757,CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496,BIIL-284, and ONO-4057, etc.

Examples of the thromboxane synthetase inhibitor include ozagrelhydrochloride, and imitrodast sodium, etc.

Examples of the thromboxane A₂ receptor antagonist include seratrodast,ramatroban, domitroban calcium dihydrate, and KT-2-962, etc.

Examples of the mediator releasing inhibitor include tranilast, sodiumcromoglicate, anlexanox, repirinast, ibudilast, tazanolast, andpemilolast potassium, etc.

Examples of the antihistamines include ketotifen fumarate, mequitazine,azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate,epinastine hydrochloride, astemizole, ebastin, cetirizine hydrochloride,bepotastine, fexofenadine, lolatadine, deslolatadine, olopatadinehydrochloride, TAK-427, ZCR-2060, NIP-530, mometasone furoate,mizolastine, BP-294, andolast, auranofin, and acribastin, etc.

Examples of the xanthine derivatives include aminophylline,thoeophyline, doxophylline, cipamfylline, and diprophilline, etc.

Examples of the anticholinergic agent include ipratropium bromide,oxitropium bromide, flutropium bromide, temiverine, tiotropium bromide,and revatropate (UK-112166), etc.

Examples of the cytokine inhibitor include suplatast tosilate (tradename: IPD), etc.

Examples of the elastase inhibitors include ONO-5046, ONO-6818, MR-889,PBI-1101, EPI-HNE-4, R-665, ZD-0892, ZD-8321, GW-311616, and AE-3763etc.

Examples of the expectorant include foeniculated ammonia spirit, sodiumhydrogencarbonate, bromhexine hydrochloride, carbocisteine, ambroxolhydrochloride, sustained release ambroxol hydrochloride, methylcysteinehydrochloride, acetyl cysteine, L-ethylcysteine hydrochloride, andtyloxapol, etc.

Examples of antibiotics include cefuroxime sodium, meropenem trihydrate,netilmicin sulfate, sisomicin sulfate, ceftibuten, PA-1806, IB-367,tobramycin, PA-1420, doxorubicin, astromicin sulfate, or cefetametpivoxil hydro chloride, etc.

Examples of antibiotics as an inhalant include PA-1806, IB-367,tobramycin, PA-1420, doxorubicin, astromicin sulfate, or cefetametpivoxil hydrochloride, etc.

The other pharmaceutical which supplement and/or enhance the preventionand/or treatment effect of the compound of the present invention is notlimited to examples as described above. With regard to otherpharmaceuticals which supplement and/or enhance the prevention and/ortreatment effect of the compound of the present invention, not only thatwhich has been found up to now but also that which will be found infuture on the basis of the above-mentioned mechanism are included.

The nomenclature of compounds of the present invention is describedbelow.

All the compounds described in the present specification were namedusing ACD/Name (registered trademark, Advanced Chemistry DevelopmentInc.) or ACD/Name Batch (registered trademark, Advanced ChemistryDevelopment Inc.), or named according to IUPAC nomenclature system. Forexample, a compound represented by

was namedN-[6-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-pyridinyl]methanesulfonamidehydrochloride.

In the present specification, “hydrochloride (or dihydrochloride)” meanseither hydrochloride or dihydrochloride, so it does not represent amixture of hydrochloride and dihydrochloride. In the presentspecification, “dihydrochloride (or trihydrochloride)” means eitherdihydrochloride or trihydrochloride, so it does not represent a mixtureof dihydrochloride and trihydrochloride. “.HCl or 2HCl” in the structuredescribed in the present specification means either HCl or 2HCl, so itdoes not represent a mixture of HCl and 2HCl. “.2HCl or 3HCl” in thestructure described in the present specification means either 2HCl or3HCl, so it does not represent a mixture of 2HCl and 3HCl.

Effect of the Invention

The compounds of the present invention represented by formula (I) hasthe antagonistic activity against chemokine receptor, especially CCR5,so they are useful in preventing and/or treating CCR5-related diseases.

The fact that the compound of the present invention has CCR5 antagonismis demonstrated, for example, by the following experiment. The totaloperation is based on the basic genetic engineering to prepare genehighly expressing cells, and the ordinary methods are utilized. Also, inthe assaying method of the present invention, in order to evaluate thecompound of the present invention, accuracy of measurement and/orsensitivity of measurement is improved as described below. The detailedexperimental methods are shown below.

(I) Inhibition Test on the Binding of RANTES to CCR5

(1) Isolation of human CCR5 Gene

Human placental cDNA is prepared using Marathon cDNA amplification kit(Clontech). PCR primers hCCR5XbaI-F1:

5′-AGCTAGTCTAGATCCGTTCCCCTACAAGAAACTCTCC-3′ (SEQ ID NO:1) andhCCR5XbaI-R1:5′-AGCTAGTCTAGAGTGCACAACTCTGACTGGGTCACCA-3′ (SEQ ID NO:2) are designedbased on the sequence of GenBank U54994.

Using the human placental cDNA as the template and using Ex Taq(Takara), PCR reaction (2 minutes at 95° C.→(30 seconds at 95° C., 45seconds at 60° C., 1 minute at 72° C.)×35 times) is carried out. Thethus amplified PCR product is subjected to a 1% agarose gelelectrophoresis, purified using QIAquick Gel Extraction Kit (QUIAGEN)and then digests with a restriction enzyme XbaI. The digested fragmentsare ligated to an expression vector pEF-BOS-bsr using DNA Ligation KitVer. 2 (Takara) and transformed into Escherichia coli DH5a. By preparingthe resulting plasmid pEF-BOS-bsr/hCCR5, its DNA sequence is verified.

-   (2) Culturing of CHO Cell

CHO-dhfr(−) is cultured using Ham's F-12 (containing fetal bovine serum(10%), penicillin (50 U/ml) and streptomycin (50 mg/ml)). Also, thetransduced cell is cultured by adding blasticidin (5 mg/ml) to the abovemedium.

-   (3) Transduction into CHO Cell

The plasmid pEF-BOS-bsr/hCCR5 is transduced into the CHO-dhfr(−) cellusing DMRIE-C reagent (Gibco BRL). After 48 hours, the medium isreplaced with a medium containing 5 mg/ml of blasticidin to carry outthe selection, thereby establishing a stably over-expressing cell.

(4) Inhibition Test on the Binding of Chemokine (RANTES, MIP-1α andMIP-1β) to CCR5 (Activity of Chemokine to Induce Transient Increase ofCa Ion).

The thus established stable CHO cell overexpressing human CCR5 (CCR5/CHOcell) is suspended in Ham's F-12 medium containing FBS (10%) and seededat a density of 3.0×10⁶ cells/well into a 96-well plate. One day afterculturing at 37° C., the culture supernatant is discarded, and Ham'sF-12 medium (containing Fura-2AM (5 μM), Probenecid (2.5 mM) and HEPES(20 mM; pH 7.4)) is dispensed in 80 μl/well portions to carry out 1 hourof incubation at 37° C. under shaded condition. After washing twice with1×Hanks/HEPES (20 mM; pH 7.4) solution, the same solution is dispensedin 100 μl/well portions. Each of the test compounds is added to the thusFura-2AM-incorporated CCR5/CHO cell, and 3 minutes thereafter, arecombinant human CCR5 ligand (RANTES, MIP-1α or MIP-1β) (PeproTach)diluted with 1×Hanks/HEPES (20 mM; pH 7.4) solution is added thereto toa final concentration (Rantes: 10 nM; MIP-1α: 30 nM; MIP-1β: 30 nM).Transient increase in the intracellular Ca²⁺ concentration induced bythe human CCR5 ligand is measured using a Ca²⁺ detector for 96 well use(Hamamatsu Photonics), and inhibition ratio (%) of the test compound iscalculated by the following calculation formula.

Inhibition ratio=(Ec−Ea)/Ec×100

-   -   Ec: measured value of Ca²⁺ transient increase by CCR5 ligand    -   Ea: measured value of Ca²⁺ transient increase by CCR5 ligand        when a test compound is added.        (II) Migration Test of Human CCR5 Expressing Cell (hCCR5-Ba/F3        cell):

(1) Establishment of Human CCR5 Expressing Cell (1-A) Isolation of HumanCCR5 Gene

The isolation is carried out according to the method of the isolation ofhuman CCR5 gene as described in the above method (I)-(1).

(1-B) Culturing of Ba/F3 Cell

Ba/F3 cells are statically cultured by using RMMI-1640 medium (GibcoBRL) containing antibiotics (Antibiotic-Antimycotic) (finalconcentration: penicillin G sodium (100 U/ml), streptomycin sulfate (100μg/ml), amphotericin B (0.25 μg/ml) (Gibco BRL), fetal bovine serum(FBS) (10%), 2-mercaptoethanol (55 μM), mouse interleukin-3 (IL-3) (5ng/ml) (Pepro Tech, Inc) in a carbon dioxide incubator (temperature: 37°C., CO₂ concentration: 5%, humidity: 95%). Exogenous gene stablehyperexpression cells are cultured in the above medium to whichblasticidin (Kaken Pharmaceutical) is added to give a finalconcentration of 10 μg/ml.

(1-C) Transformation to Ba/F3 Cell

A plasmid for human CCR5 expression (pEF-BOS-bsr/hCCR5) is digested withAatII for linearization. The linearized plasmid is purified by QIA quickPCR Purification Kit (QIAGEN), and introduces into Ba/F3 cells byelectroporation (Gene Pulser (BIO RAD), 960 μF/250V). The cells areseeded into a 96-well culture plate at a density of 1,000, 100, 10cells/100 μl/well, and cultured for 48 hours. Then, blasticidin is addedthereto to give a final concentration of 10 μg/ml, followed by cloningof a blasticidin-resistant cell line to thereby establish a stable cloneoverexpressing the transfected exogenous gene (hCCR5-Ba/F3 cell).

(1-D) Analysis of CCR5 Expression

The human CCR5 expression level in the clone obtained by the methoddescribed in the above (1-C) is detected with FAC Sort (trade name,Becton, Dickinson) by detecting the cells with a fluorescenceisothiocyanate (FITC)-labeled anti-human CCR5 antibody (BD Pharmingen)and analyzed. In this connection, FITC-labeled mouse IgG2aκ (BDPharmingen) is used as an isotype control antibody.

(2) Cell Migration Test

Influence of a test compound on the migration ability of the human CCR5expressing Ba/F3 cell against RANTES, MIP-1α or MIP-1β is examined.First, 0.3 ml of 0 or 3 nM chemokine (RANTES, MIP-1α orMIP-1β)-containing medium is respectively added to the low room of ChemoT×96 well plate (Neuro Probe). Next, a filter (pore size: 5 μm) is setand a mixture solution (1×10⁵ cells/well) of the test compound and theCCR5-Ba/F3 cell prepared in advance is added at 65 μl. The test compoundto be added is prepared by diluting it with 0.1% DMSO-containing mediumto give a final concentration on the filter of 0, 0.01, 0.03, 0.1 or 0.3μM. These cells are cultured in a CO₂ incubator (37° C., 5% CO₂,relative humidity: 95%) for 3 hours, and then the medium and unmigratedcells on the filter are eliminated. Furthermore, the filter is removed,the microplate is centrifuged (1,500 rpm, 10 min, RT) and thesupernatant is removed by decantation. The cells on the microplate aresuspended in 100 μl of a phosphate buffer (PBS), and 1/10 portionthereof is further diluted with 90 μl of PBS, moves on a white plate forfluorescence assay, and uses as an assay sample for migrated cellnumbers (final: 100 μl/well).

Next, Cell Titer-Glo Reagent (trade name, Promega) which is previouslyprepared at room temperature is added to the above assay sample formigrated cell numbers (100 μl/well), followed by gently mixing (300 rpm,2 min with KA-SCHUTTLER MTS4) for lysating the cells, the mixture isincubated at room temperature for 10 minutes, and the fluorescence ismeasured with wallac ARVO SX 1420 MULTILABEL COUNTER (trade name, PerkinElmer) (detection by count/second).

The migrated cell numbers (naturally falling cell numbers) at achemokine concentration of 0 nmol/l is used as the background, and theinhibition ratio of the test compound against the 0.1% DMSO controlgroup is calculated.

The inhibition migration ratio (%) of the test compound is calculated bythe following equation:

${{Inhibition}\mspace{14mu} {ratio}} = {\frac{\left( {{Ec} - {Ea}} \right)}{Ec} \times 100}$

-   -   Ec: (fluorescence measured value at the addition of 0.1%        DMSO)−(fluorescence measured value of the naturally falling        cells)    -   Ea: (fluorescence measured value at the addition of the test        compound)−(fluorescence measured value of the naturally falling        cells)

BEST MODE FOR CARRYING OUT THE INVENTION

The following Preparation Examples, Biological Examples and FormulationExamples are intended to illustrate the present invention, but do notlimit them.

In chromatographic separations and TLC, the solvents in parenthesis showthe eluting and developing solvents and the ratios of the solvents usedare by volume.

NMR is a measured value of ¹H NMR. The solvents in parenthesis in NMRshow the solvents used for measurement.

Preparation Example Example 1N-[6-(4-formylphenoxy)pyridin-3-yl]methanesulfonamide

{4-[(5-nitropyridin-2-yl)oxy]phenyl}methanol was subjected to reductionof nitro group by using zinc and acetic acid, the obtained compoundreacted with methanesulfonyl chloride in pyridine, and the obtainedcompound was subjected to oxidation by using manganese dioxide to givethe title compound having the following physical data.

TLC: Rf 0.67 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 3.04, 6.56, 7.05, 7.29, 7.80, 7.94, 8.08, 9.99.

Example 2 N-butyl-N′-(2,4-difluorophenyl)-N-piperidin-4-ylureahydrochloride

To a solution of tert-butyl 4-(butylamino)piperidin-1-carboxylate (1 g)in dimethylacetamide (13 ml) was added triethylamine (1.6 ml) and2,4-difluorophenyl isocyanate (907 mg). The reaction mixture was stirredfor 5 minutes at room temperature. To reaction mixture was added asaturated aqueous solution of sodium hydrogen carbonate, and extractedwith ethyl acetate. The extract was washed with water and brine, driedover anhydrous sodium sulfate, and concentrated. To the solution of theobtained compound (1.28 g) in ethyl acetate (2 ml) was added 4N hydrogenchloride in ethyl acetate solution (10 ml). The reaction mixture wasstirred for 20 minutes at room temperature, and concentrated. Theobtained residue was washed with tert-butyl methyl ether, dried to givethe title compound having the following physical data.

TLC: Rf 0.52 (dichloromethane:methanol:acetic acid=5:1:0.1);

NMR (CD₃OD): δ 0.99, 1.34-1.47, 1.60-1.71, 1.95-2.01, 2.08-2.22,3.03-3.13, 3.27-3.34, 3.44-3.50, 4.13, 7.00, 7.37, 8.01.

Example 3N-[6-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-pyridinyl]methanesulfonamidehydrochloride (or dihydrochloride)

To a solution of the compound prepared in Example 1 (95 mg) and thecompound prepared in Example 2 (80 mg) in dimethylformamide (1.5 ml) wasadded acetic acid (0.15 ml) and sodium triacetoxyborohydride (116 mg).The reaction mixture was stirred for 18 hours at room temperature. Thereaction mixture was added a saturated aqueous solution of sodiumhydrogen carbonate, and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate, and concentrated. The obtainedresidue was purified by column chromatography on silica gel (ethylacetate:methanol=10:1). To a solution of the obtained compound was added4N hydrogen chloride in ethyl acetate solution. The reaction mixture wasconcentrated to give the title compound (115 mg) having the followingphysical data.

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.35-1.48, 1.58-1.70, 1.95-2.08, 2.18-2.34, 3.00,3.08-3.20, 3.25-3.34, 3.57-3.65, 4.19, 4.34, 6.89-7.03, 7.09, 7.25,7.38, 7.60, 7.85, 8.06.

Examples 3(1)-3(107)

By the same procedure as described in Example 3 using the correspondingamine compounds and the corresponding aldehyde compounds, the followingcompounds of the present invention were obtained.

Example 3(1)N-{4-[(6-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-3-pyridinyl)oxy]phenyl}methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.30 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.99, 1.30-1.50, 1.60-1.80, 1.90-2.10, 2.20-2.40, 2.97,3.20-3.40, 3.60-3.70, 4.20, 4.47, 6.92-7.02, 7.09-7.12, 7.31-7.40,7.47-7.58, 8.45.

Example 3(2)N-{4-[4-({4-[{[(2-hydroxybutyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamidehydrochloride

TLC: Rf 0.41 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.89, 1.20-1.42, 1.55-1.70, 2.05-2.17, 2.95, 3.08-3.28,3.37-3.50, 4.21, 4.51, 7.00, 7.02, 7.21-7.30, 7.41, 7.44-7.55.

Example 3(3)N-{4-[4-({4-[butyl({[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamidedihydrochloride

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.31-1.42, 1.50-1.72, 1.91-2.01, 2.15-2.31, 2.95,3.10-3.32, 3.51-3.60, 3.87, 4.23, 4.30, 4.35, 7.03, 7.06, 7.29, 7.53,7.98, 8.12.

Example 3(4)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-methylbenzamidehydrochloride

TLC: Rf 0.90 (chloroform:methanol=4:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.10-2.30, 2.91,2.95, 3.00-3.20, 3.20-3.40, 3.50-3.60, 4.15, 4.29, 7.02-7.09, 7.12,7.29, 7.50, 7.78.

Example 3(5)N-{4-[4-({4-[{[(trans-4-hydroxycyclohexyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamidehydrochloride

TLC: Rf 0.46 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.00-1.18, 1.21-1.37, 1.55-1.68, 1.71-1.89, 2.04-2.15,2.95, 3.04-3.18, 3.38-3.54, 4.21, 4.60, 6.98-7.07, 7.18-7.23, 7.28,7.41, 7.45-7.53.

Example 3(6) N-[4-(4-{[4-(3-butenyl{[(2-hydroxybutyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamidehydrochloride

TLC: Rf 0.51 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.95, 1.30-1.58, 1.90-2.00, 2.07-2.24, 2.28-2.38, 2.95,3.02-3.35, 3.50-3.60, 4.12, 4.28, 5.05, 5.11, 5.81, 7.03, 7.06, 7.29,7.50.

Example 3(7)N-butyl-N′-(2,4-difluorophenyl)-N-(1-{4-[4-(4-morpholinylsulfonyl)phenoxy]benzyl}-4-piperidinyl)ureahydrochloride

TLC: Rf 0.60 (dichloromethane:methanol=20:1);

NMR (CD₃OD): δ 0.99, 1.39-1.43, 1.60-1.70, 2.00-2.05, 2.16-2.30,2.94-2.97, 3.06-3.28, 3.29-3.36, 3.52-3.61, 3.69-3.72, 4.13, 4.23,6.90-7.03, 7.20, 7.23, 7.37, 7.58, 7.78.

Example 3(8)N-butyl-2-(2,4-difluorophenyl)-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]acetamidehydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1);

NMR (d₆-DMSO): δ 0.92, 1.20-1.40, 1.40-1.60, 1.70-1.90, 2.20-2.40,2.90-3.10, 2.97, 3.15-3.30, 3.30-3.50, 3.71, 4.05-4.30, 6.94-7.09,7.12-7.25, 7.57, 9.34, 10.50.

Example 3(9)N-{4-[(5-{[4-(butyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.16 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.96, 1.30-1.45, 1.50-1.65, 1.90-2.05, 2.20-2.35, 2.98,3.10-3.40, 3.50-3.70, 4.00, 4.20, 4.36, 7.09-7.16, 7.32, 7.95, 8.06,8.08, 8.31.

Example 3(10)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfanyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamidehydrochloride

TLC: Rf 0.67 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.60-1.79, 2.10-2.20, 2.51, 2.95, 3.08-3.20, 3.42-3.55,4.22, 4.64, 6.95, 7.02, 7.03, 7.15-7.31, 7.39, 7.42.

Example 3(11)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfanyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamidehydrochloride

TLC: Rf 0.67 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.12-2.20, 2.51, 2.95, 3.04-3.22, 3.42-3.57,4.22, 4.64, 6.89-7.10, 7.17-7.32, 7.34-7.49.

Example 3(12)N-butyl-2,4-difluoro-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]benzamidehydrochloride

TLC: Rf 0.41 (chloroform:methanol=10:1);

NMR (d₆-DMSO): δ 0.70-0.90, 1.10-1.30, 1.40-1.60, 1.75-1.90, 2.30-2.55,2.80-3.05, 2.96, 3.10-3.45, 4.00, 4.17, 7.00, 7.01-7.04, 7.12,7.19-7.30, 7.42, 7.57, 9.35.

Example 3(13)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfinyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamidehydrochloride

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.67-1.83, 2.14-2.23, 2.84, 2.95, 3.10-3.21, 3.46-3.55,4.23, 4.67, 6.96, 7.00, 7.02, 7.23, 7.28, 7.43, 7.54, 7.84.

Example 3(14)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfinyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamidehydrochloride

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.14-2.25, 2.86, 2.95, 3.08-3.21, 3.47-3.55,4.23, 4.66, 6.96, 7.01, 7.02, 7.20-7.30, 7.42, 7.51, 7.66, 7.70-7.80.

Example 3(15)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfonyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamidehydrochloride

TLC: Rf 0.54 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.70-1.88, 2.14-2.23, 2.95, 3.10-3.20, 3.16, 3.46-3.55,4.23, 4.64, 6.96, 7.01, 7.02, 7.24, 7.28, 7.43, 7.57, 8.08.

Example 3(16)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfonyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamidehydrochloride

TLC: Rf 0.54 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.80, 2.17-2.28, 2.95, 3.10-3.21, 3.19, 3.45-3.55,4.23, 4.67, 6.96, 7.01, 7.02, 7.24, 7.28, 7.42, 7.66, 7.78, 7.89, 8.05.

Example 3(17)N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-methoxyphenyl]methanesulfonamidehydrochloride

TLC: Rf 0.50 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.15-2.30, 2.99,3.05-3.20, 3.20-3.40, 3.50-3.60, 3.74, 4.15, 4.25, 6.85-6.95, 6.99,7.03, 7.38, 7.43.

Example 3(18)5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.41 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.45, 1.55-1.70, 1.95-2.10, 2.15-2.35, 2.98,3.05-3.20, 3.25-3.35, 3.50-3.65, 4.15, 4.34, 7.09-7.18, 7.33, 7.86,8.03, 8.28.

Example 3(19)5-{[(butyl{1-[(5-{4-[(methylsulfonyl)amino]phenoxy}-2-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidedihydrochloride

TLC: Rf 0.36 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.99, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.20-2.40, 2.96,3.20-3.40, 3.60-3.70, 4.20, 4.45, 7.10, 7.15, 7.33, 7.44-7.50, 7.87,8.44.

Example 3(20)5-[({butyl[1-(4-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.55-1.70, 1.90-2.10, 2.10-2.30, 2.99,3.05-3.20, 3.20-3.40, 3.50-3.60, 3.74, 4.15, 4.25, 6.87, 6.92, 7.03,7.14, 7.42, 7.85.

Example 3(21)5-[({butyl[1-(4-{2-chloro-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.55-1.70, 1.90-2.10, 2.10-2.30, 3.01,3.10-3.20, 3.25-3.35, 3.50-3.60, 4.15, 4.28, 6.99, 7.13, 7.14, 7.24,7.43, 7.50, 7.85.

Example 3(22)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-(2-hydroxyethyl)benzenesulfonamidehydrochloride

TLC: Rf 0.69 (dichloromethane:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.36-1.43, 1.59-1.70, 1.98-2.03, 2.18-2.30, 2.96,3.09-3.30, 3.54, 3.54-3.61, 4.16, 4.33, 6.90-7.03, 7.16, 7.20, 7.37,7.59, 7.86.

Example 3(23)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzenesulfonamidedihydrochloride

TLC: Rf 0.56 (dichloromethane:methanol=2:1);

NMR (CD₃OD): δ 0.98, 1.33-1.46, 1.59-1.70, 1.96-2.00, 2.20-2.35, 2.93,3.05-3.12, 3.17-3.30, 3.52-3.56, 4.18, 4.30, 6.89-7.03, 7.19, 7.37,7.61, 7.90.

Example 3(24)N-{4-[4-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamidehydrochloride

TLC: Rf 0.76 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 2.95, 3.05-3.20, 3.40-3.55, 4.21,4.65, 6.85-6.96, 6.99-7.04, 7.28, 7.35-7.40, 7.41, 7.51-7.58.

Example 3(25)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-methylbenzenesulfonamidehydrochloride

TLC: Rf 0.63 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.36-1.46, 1.59-1.70, 1.99-2.04, 2.17-2.30, 2.53,3.07-3.17, 3.24-3.35, 3.57-3.61, 4.15, 4.33, 6.89-7.03, 7.16, 7.20,7.36, 7.57, 7.83.

Example 3(26)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N,N-dimethylbenzenesulfonamidehydrochloride

TLC: Rf 0.67 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.34-1.46, 1.60-1.70, 1.99-2.03, 2.19-2.30, 2.68,3.09-3.17, 3.25-3.36, 3.57-3.61, 4.16, 4.33, 6.89-7.03, 7.18, 7.21,7.36, 7.59, 7.78.

Example 3(27)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-(2-methoxyethyl)benzenesulfonamidehydrochloride

TLC: Rf 0.60 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.34-1.46, 1.60-1.70, 1.99-2.03, 2.19-2.30, 3.03,3.09-3.17, 3.26, 3.26-3.30, 3.36, 3.56-3.61, 4.16, 4.33, 6.89-7.03,7.14, 7.19, 7.37, 7.57, 7.85.

Example 3(28)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-tetrahydro-2H-pyran-4-ylbenzenesulfonamidehydrochloride

TLC: Rf 0.57 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.36-1.53, 1.63-1.68, 2.01-2.04, 2.21-2.25,3.07-3.37, 3.57-3.61, 3.81-3.85, 4.14, 4.33, 4.80, 6.89-7.03, 7.14,7.19, 7.36, 7.57, 7.87.

Example 3(29)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.60-1.80, 2.12-2.23, 2.97, 3.11-3.24, 3.48-3.58, 4.27,4.67, 6.95, 7.06, 7.11, 7.21, 7.28-7.35, 7.48-7.60, 7.90, 8.18.

Example 3(30)N-[5-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-2-pyridinyl]methanesulfonamidehydrochloride

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.34-1.44, 1.58-1.68, 1.96-2.05, 2.15-2.31,3.03-3.18, 3.28, 3.25-3.33, 3.52-3.60, 4.17, 4.30, 6.88-7.04, 7.12,7.14, 7.37, 7.51-7.60, 8.10.

Example 3(31)5-({[butyl(1-{4-[4-(4-morpholinylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.48 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.20-2.35, 2.96,3.00-3.20, 3.20-3.40, 3.50-3.60, 3.71, 4.10, 4.33, 7.11-7.24, 7.59,7.78, 7.87.

Example 3(32)5-[({butyl[1-(4-{4-[(tetrahydro-2H-pyran-4-ylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.20-2.30,3.10-3.20, 3.20-3.40, 3.50-3.70, 3.80-3.90, 4.15, 4.33, 7.11-7.21, 7.60,7.87, 7.88.

Example 3(33)5-[({butyl[1-(4-{2,6-dimethyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.34 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.08, 2.20-2.30,2.99, 3.00-3.20, 3.20-3.40, 3.50-3.60, 4.15, 4.26, 6.86, 7.04, 7.14,7.45, 7.85.

Example 3(34)5-[({butyl[1-(4-{4-[methyl(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.40 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.15-2.30, 2.99,3.00-3.20, 3.20-3.40, 3.30, 3.50-3.60, 4.15, 4.30, 7.05-7.18, 7.45,7.52, 7.86.

Example 3(35)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]benzyl}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.33 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.15-2.30, 2.91,3.00-3.20, 3.20-3.40, 3.50-3.60, 3.98, 4.15, 4.27, 7.10-7.20, 7.34,7.44, 7.85.

Example 3(36)5-{[(butyl{1-[(3,5-dimethyl-1-{4-[(methylsulfonyl)amino]phenyl}-1H-pyrazol-4-yl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidedihydrochloride

TLC: Rf 0.20 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.34-1.47, 1.60-1.72, 1.98-2.10, 2.27-2.50, 2.39,2.43, 3.04, 3.12-3.40, 3.65-3.75, 4.24, 4.29, 7.15, 7.43, 7.49, 7.87.

Example 3(37)5-({[(1-{4-[4-(aminosulfonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.33 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.35-1.47, 1.58-1.70, 1.97-2.08, 2.18-2.32,3.08-3.20, 3.23-3.35, 3.52-3.63, 4.16, 4.33, 7.10-7.24, 7.58, 7.64,7.90.

Example 3(38)5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.47, 1.60-1.71, 1.98-2.10, 2.20-2.36, 2.53,3.08-3.20, 3.26-3.35, 3.52-3.64, 4.18, 4.33, 7.14, 7.16, 7.19, 7.60,7.83, 7.86.

Example 3(39)5-[({butyl[1-(4-{4-[(dimethylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.49, 1.59-1.72, 1.97-2.09, 2.19-2.38, 2.68,3.08-3.21, 3.23-3.35, 3.58-3.64, 4.16, 4.34, 7.14, 7.19, 7.21, 7.60,7.79, 7.86.

Example 3(40)N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-methylphenyl]methanesulfonamidehydrochloride

TLC: Rf 0.39 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.55-1.70, 1.90-2.10, 2.10-2.30, 2.16,2.96, 3.00-3.20, 3.20-3.40, 3.50-3.60, 4.15, 4.27, 6.91-6.99, 7.13,7.20, 7.36, 7.46.

Example 3(41)5-[({butyl[1-(4-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

White amorphous powder;

TLC: Rf 0.28 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.55-1.70, 1.90-2.10, 2.10-2.30, 2.16,2.96, 3.00-3.20, 3.20-3.40, 3.50-3.60, 4.10, 4.26, 6.91-6.97, 7.11-7.20,7.46, 7.86.

Example 3(42)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]benzoicacid hydrochloride

TLC: Rf 0.49 (dichloromethane:methanol=5:1);

NMR (CD₃OD): δ 0.98, 1.35-1.45, 1.60-1.70, 1.98-2.03, 2.20-2.30,3.10-3.34, 3.56-3.60, 4.16, 4.33, 7.07, 7.14, 7.18, 7.57, 7.86, 8.04.

Example 3(43)5-{[(butyl{1-[(6-{2-chloro-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.33 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.55-1.70, 1.90-2.10, 2.20-2.40, 3.02,3.10-3.25, 3.25-3.40, 3.50-3.60, 4.20, 4.35, 7.10-7.26, 7.43, 7.86,8.09, 8.26.

Example 3(44)5-{[(butyl{1-[(6-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.33-1.47, 1.58-1.71, 1.97-2.08, 2.20-2.38, 3.01,3.07-3.21, 3.25-3.35, 3.55-3.65, 3.72, 4.18, 4.35, 6.90, 7.04-7.19,7.86, 8.08, 8.29.

Example 3(45)5-({[butyl(1-{4-[4-(methylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.35-1.48, 1.59-1.70, 1.98-2.08, 2.19-2.34, 3.12,3.08-3.21, 3.25-3.35, 3.55-3.64, 4.16, 4.34, 7.14, 7.21, 7.22, 7.61,7.86, 7.95.

Example 3(46)4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]benzoicacid hydrochloride

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.67-1.80, 2.12-2.22, 3.12-3.24, 3.48-3.55, 4.26, 4.68,6.95, 7.05, 7.14, 7.22, 7.33, 7.47-7.60, 8.03.

Example 3(47)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoicacid hydrochloride

TLC: Rf 0.66 (chloroform:methanol=3:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.10-2.35,3.05-3.20, 3.25-3.35, 3.50-3.60, 3.82, 4.10, 4.28, 6.98, 7.09, 7.15,7.47, 7.77, 7.75, 7.86.

Example 3(48)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-chlorobenzoicacid hydrochloride

TLC: Rf 0.65 (chloroform:methanol=3:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.20-2.35,3.05-3.20, 3.25-3.35, 3.50-3.60, 4.10, 4.33, 7.10-7.17, 7.57, 7.86,7.95, 8.14.

Example 3(49)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-nitrobenzoicacid hydrochloride

TLC: Rf 0.51 (chloroform:methanol=3:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.20-2.35,3.00-3.15, 3.20-3.35, 3.50-3.60, 4.15, 4.29, 7.10-7.20, 7.58, 7.86,8.20, 8.56.

Example 3(50)5-[({butyl[1-(4-{3-methoxy-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.47, 1.58-1.70, 1.97-2.08, 2.17-2.31, 2.91,3.06-3.20, 3.24-3.35, 3.51-3.63, 3.86, 4.13, 4.29, 6.57, 6.81, 7.10,7.14, 7.36, 7.51, 7.86.

Example 3(51)5-[({butyl[1-(4-{3-chloro-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.48, 1.60-1.72, 1.98-2.08, 2.12-2.31, 3.00,3.08-3.20, 3.24-3.35, 3.52-3.62, 4.15, 4.31, 7.00, 7.10-7.20, 7.51-7.59,7.86.

Example 3(52)5-({[butyl(1-{[6-(4-methoxyphenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.39 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.20-2.35,3.05-3.20, 3.20-3.35, 3.50-3.65, 3.81, 4.20, 4.34, 6.97-7.20, 7.86,8.05, 8.31.

Example 3(53)4-{[5-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}benzoicacid hydrochloride (or dihydrochloride)

TLC: Rf 0.63 (chloroform:methanol=3:1);

NMR (CD₃OD): δ 0.97, 1.30-1.45, 1.55-1.70, 1.85-2.00, 2.05-2.20,2.65-2.85, 3.20-3.40, 4.05, 4.10, 7.09-7.21, 7.89, 7.97, 8.07, 8.23.

Example 3(54)N-(4-{4-[(4-{phenyl[(tetrahydro-2H-pyran-4-ylamino)carbonyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamidehydrochloride

TLC: Rf 0.46 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.24-1.40, 1.55-1.75, 2.05-2.15, 2.95, 3.04-3.18,3.34-3.50, 3.68-3.84, 4.21, 4.60, 6.98-7.04, 7.22, 7.28, 7.41,7.45-7.56.

Example 3(55)5-{[(butyl{1-[(5-{4-[(methylsulfonyl)amino]phenoxy}-2-pyrazinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidedihydrochloride

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.99, 1.34-1.48, 1.59-1.72, 1.98-2.08, 2.21-2.38, 2.97,3.17-3.38, 3.62-3.71, 4.18, 4.46, 7.14, 7.18, 7.33, 7.67, 8.24, 8.54.

Example 3(56)5-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-2-[(methylsulfonyl)amino]benzoicacid hydrochloride

TLC: Rf 0.48 (dichloromethane:methanol=5:1);

NMR (CD₃OD): δ 0.96, 1.28-1.47, 1.59-1.71, 1.95-2.06, 2.18-2.37, 3.02,3.00-3.20, 3.24-3.35, 3.50-3.61, 4.15, 4.30, 7.08, 7.14, 7.25, 7.51,7.67-7.72, 7.86.

Example 3(57)2-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzoicacid hydrochloride

TLC: Rf 0.35 (dichloromethane:methanol=5:1);

NMR (CD₃OD): δ 0.98, 1.31-1.48, 1.54-1.71, 1.94-2.04, 2.12-2.36, 3.00,3.00-3.18, 3.20-3.35, 3.51-3.61, 4.15, 4.27, 6.98, 7.08, 7.14,7.41-7.52, 7.82, 7.84.

Example 3(58)N-[4-(4-{[4-(butyl{[(3,4-dicyanophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamidehydrochloride

TLC: Rf 0.41 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.96, 1.31-1.42, 1.52-1.64, 1.98-2.07, 2.21-2.39, 2.95,3.04-3.21, 3.28-3.35, 3.52-3.61, 4.19, 4.30, 7.03, 7.06, 7.29, 7.52,7.79-7.89, 8.11.

Example 3(59)N-[4-(4-{[4-(butyl{[(4-cyano-2,5-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamidehydrochloride

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.35-1.46, 1.55-1.68, 1.95-2.06, 2.19-2.37, 2.95,3.08-3.21, 3.24-3.38, 3.52-3.61, 4.18, 4.29, 7.03, 7.06, 7.29, 7.50,7.60, 7.87.

Example 3(60)5-({[butyl(1-{[6-(4-cyanophenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.54 (dichloromethane:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.36-1.43, 1.59-1.67, 2.00-2.04, 2.21-2.32,2.99-3.18, 3.26-3.30, 3.56-3.63, 4.14, 4.36, 7.14, 7.21, 7.33, 7.80,7.86, 8.06, 8.29.

Example 3(61)3-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamidehydrochloride

TLC: Rf 0.33 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.63-1.80, 2.14-2.23, 2.95, 3.10-3.22, 3.47-3.55, 4.23,4.69, 7.01, 7.03, 7.25-7.37, 7.40-7.60, 7.72.

Example 3(62)4-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]benzamidehydrochloride

TLC: Rf 0.33 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.50-1.70, 1.95-2.10, 2.10-2.30, 2.95,3.00-3.20, 3.20-3.40, 3.50-3.60, 4.20, 4.30, 7.02-7.08, 7.29, 7.47-7.52,7.80.

Example 3(63)N-{4-[4-({4-[butyl({[2,4-difluoro-5-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamidehydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.95-2.05, 2.10-2.30, 2.95,3.00-3.20, 3.20-3.50, 3.50-3.70, 3.70-3.80, 4.10, 4.29, 7.02-7.08, 7.15,7.29, 7.46, 7.49.

Example 3(64)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-(2-methoxyethyl)benzamidehydrochloride

TLC: Rf 0.44 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.75, 1.90-2.10, 2.15-2.35, 2.95,3.00-3.20, 3.20-3.40, 3.50-3.60, 3.55, 4.13, 4.28, 7.02-7.08, 7.13,7.29, 7.49, 7.78.

Example 3(65)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N,N-dimethylbenzamidehydrochloride

TLC: Rf 0.46 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.80, 1.90-2.10, 2.20-2.30, 2.95,2.97, 3.05-3.20, 3.10, 3.25-3.35, 3.50-3.60, 4.15, 4.29, 7.02-7.08,7.14, 7.29, 7.43, 7.50.

Example 3(66)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-(2-hydroxyethyl)benzamidehydrochloride

TLC: Rf 0.38 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.10-2.30, 2.95,3.05-3.20, 3.20-3.40, 3.50, 3.50-3.60, 3.67, 4.15, 4.27, 7.02-7.07,7.13, 7.29, 7.50, 7.81.

Example 3(67)N-{4-[(5-{[4-(butyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3-chlorophenyl}methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.57 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.96, 1.30-1.45, 1.50-1.65, 1.90-2.10, 2.20-2.40, 3.02,3.10-3.50, 3.50-3.65, 4.08, 4.25, 4.37, 7.16, 7.24-7.26, 7.43, 8.12,8.16, 8.23, 8.28.

Example 3(68)N-{4-[(5-{[4-(butyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3,5-dimethylphenyl}methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.56 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.96, 1.30-1.50, 1.50-1.65, 1.90-2.05, 2.08, 2.20-2.40,2.98, 3.10-3.40, 3.55-3.65, 4.06, 4.25, 4.37, 7.05, 7.08, 8.13, 8.16,8.20, 8.33.

Example 3(69)5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.43 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.32-1.45, 1.58-1.70, 1.95-2.07, 2.14, 2.20-2.40,2.98, 3.08-3.21, 3.24-3.37, 3.55-3.64, 4.20, 4.36, 7.02-7.25, 7.86,8.14, 8.34.

Example 3(70)5-{[(butyl{1-[(6-{2,6-dimethyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.32-1.45, 1.58-1.70, 1.95-2.08, 2.08, 2.21-2.39,2.98, 3.08-3.21, 3.24-3.35, 3.55-3.65, 4.20, 4.36, 7.05, 7.08, 7.14,7.86, 8.14, 8.33.

Example 3(71)5-[({2-butynyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.82, 2.01-2.12, 2.12-2.31, 2.95, 3.08-3.19, 3.52-3.61,4.10, 4.29, 4.32, 7.03, 7.06, 7.15, 7.29, 7.51, 7.96.

Example 3(72)2,4-difluoro-5-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](propyl)amino]carbonyl}amino)benzamidehydrochloride

TLC: Rf 0.51 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.62-1.75, 1.98-2.08, 2.18-2.30, 2.95, 3.02-3.18,3.21-3.33, 3.52-3.60, 4.14, 4.28, 7.03, 7.06, 7.14, 7.29, 7.50, 7.85.

Example 3(73)N-{4-[4-({4-[butyl({[2,4-difluoro-5-(hydroxymethyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamidehydrochloride

TLC: Rf 0.80 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.75, 1.90-2.10, 2.20-2.35, 2.96,3.05-3.20, 3.20-3.40, 3.50-3.65, 4.20, 4.29, 4.60, 6.97, 7.03, 7.06,7.29, 7.46, 7.52.

Example 3(74)2,4-difluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.93, 1.28-1.45, 1.60-1.71, 1.97-2.08, 2.20-2.38, 2.98,3.08-3.22, 3.25-3.35, 3.55-3.64, 4.18, 4.35, 7.09-7.20, 7.33, 7.86,8.08, 8.31.

Example 3(75)5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.32, 1.28-1.45, 1.57-1.70, 1.95-2.08, 2.21-2.38,3.11, 3.08-3.21, 3.25-3.35, 3.52-3.64, 4.18, 4.35, 7.07-7.17, 7.33,7.86, 8.08, 8.31.

Example 3(76)N-(4-{[5-({4-[{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}(pentyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.92, 1.28-1.42, 1.52-1.64, 1.92-2.04, 2.20-2.38, 2.98,3.10-3.29, 3.52-3.64, 4.04, 4.24, 4.37, 7.11, 7.16, 7.34, 8.05, 8.12,8.14, 8.34.

Example 3(77)N-{4-[(5-{[4-(butyl{[(1-ethyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.28-1.42, 1.52, 1.50-1.64, 1.90-2.02, 2.20-2.38,2.98, 3.04-3.29, 3.51-3.64, 4.24, 4.30-4.44, 7.13, 7.16, 7.34,8.05-8.16, 8.21, 8.34.

Example 3(78)5-[({butyl[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.48 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.55-1.70, 2.00-2.10, 2.20-2.40,3.05-3.20, 3.15, 3.25-3.40, 3.50-3.70, 4.20, 4.36, 7.14, 7.22, 7.40,7.86, 8.01, 8.07, 8.29.

Example 3(79)2,4-difluoro-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.44 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.94, 1.30-1.45, 1.60-1.75, 2.00-2.10, 2.15-2.40,3.00-3.20, 3.15, 3.20-3.40, 3.50-3.70, 4.15, 4.35, 7.14, 7.22, 7.39,7.86, 8.01, 8.05, 8.29.

Example 3(80)2,4-difluoro-5-({[{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.46 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.45, 1.60-1.75, 1.95-2.10, 2.13, 2.15-2.30,2.98, 3.10-3.40, 3.55-3.65, 4.15, 4.34, 7.01-7.21, 7.86, 8.04, 8.26.

Example 3(81)5-({[{1-[(6-{2,6-dimethyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.45, 1.60-1.70, 2.00-2.10, 2.06, 2.15-2.30,2.99, 3.00-3.40, 3.50-3.70, 4.10, 4.32, 7.03, 7.08, 7.14, 7.86, 7.98,8.20.

Example 3(82)5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.46 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.45, 1.33, 1.60-1.70, 2.00-2.10, 2.20-2.40,3.00-3.40, 3.11, 3.50-3.70, 4.15, 4.34, 7.08-7.17, 7.32, 7.86, 8.03,8.28.

Example 3(83)5-({[{1-[(6-{2-chloro-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.60-1.75, 2.00-2.10, 2.15-2.25, 3.02,3.05-3.35, 3.50-3.70, 4.10, 4.33, 7.14-7.28, 7.42, 7.86, 8.00, 8.20.

Example 3(84)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.82, 2.11-2.21, 3.00, 3.10-3.24, 3.48-3.57, 3.71,4.31, 4.67, 6.87-7.00, 7.02-7.09, 7.12, 7.20, 7.32, 7.45-7.59, 8.03,8.26.

Example 3(85)N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamidehydrochloride (or dihydrochloride)

Amorphous powder;

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.67-1.82, 2.11-2.24, 3.00, 3.12-3.24, 3.50-3.57, 3.71,4.30, 4.67, 6.84-6.97, 7.01-7.08, 7.11, 7.35, 7.48-7.61, 8.02, 8.24.

Example 3(86)5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2-chloro-4-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.40 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.55-1.70, 1.90-2.10, 2.12, 2.20-2.40,2.97, 3.00-3.20, 3.25-3.35, 3.50-3.70, 4.20, 4.33, 7.00-7.21, 7.32,7.66, 8.01, 8.24.

Example 3(87)5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2-chloro-4-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.40 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.33, 1.35-1.50, 1.60-1.70, 1.95-2.10, 2.20-2.40,3.10, 3.10-3.20, 3.20-3.40, 3.50-3.65, 4.15, 4.33, 7.08-7.12, 7.30-7.34,7.65, 7.99, 8.24.

Example 3(88)5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]-2-methylphenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.62 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.33, 1.28-1.45, 1.59-1.70, 1.97-2.08, 2.12,2.18-2.34, 3.11, 3.06-3.20, 3.25-3.35, 3.52-3.63, 4.12, 4.33, 7.00,7.07, 7.13, 7.15, 7.20, 7.86, 8.01, 8.24.

Example 3(89)5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluoro-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.30-1.47, 1.58-1.70, 1.95-2.07, 2.13, 2.20-2.37,2.91, 2.98, 3.04-3.21, 3.22-3.35, 3.52-3.64, 4.18, 4.34, 7.01-7.24,7.79, 8.06, 8.27.

Example 3(90)5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluoro-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.33, 1.30-1.47, 1.59-1.70, 1.98-2.05, 2.20-2.38,2.91, 3.11, 3.07-3.21, 3.22-3.35, 3.52-3.64, 4.18, 4.35, 7.08-7.16,7.32, 7.79, 8.06, 8.29.

Example 3(91)5-{[(butyl{1-[(6-{2-chloro-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluoro-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.32-1.45, 1.58-1.70, 1.97-2.05, 2.20-2.37, 2.91,3.02, 3.04-3.21, 3.22-3.35, 3.51-3.62, 4.18, 4.34, 7.06-7.29, 7.42,7.79, 8.06, 8.23.

Example 3(92)5-{[(butyl{1-[(6-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluoro-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.32-1.45, 1.58-1.70, 1.95-2.05, 2.19-2.37, 2.91,3.00, 3.04-3.21, 3.22-3.35, 3.54-3.62, 3.72, 4.18, 4.34, 6.90,7.04-7.17, 7.79, 8.06, 8.27.

Example 3(93)2-(5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorophenyl)acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.42 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.50-1.70, 1.95-2.10, 2.15-2.30, 2.97,3.05-3.20, 3.20-3.40, 3.50-3.60, 3.53, 4.10, 4.33, 7.00, 7.08-7.14,7.30-7.34, 7.97, 8.24.

Example 3(94)2-[2,4-difluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.43 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.55-1.75, 1.90-2.10, 2.15-2.35, 2.97,3.10-3.20, 3.20-3.40, 3.50-3.60, 3.53, 4.15, 4.33, 7.00, 7.08-7.14,7.30-7.34, 7.99, 8.25.

Example 3(95)5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluoro-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.41 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.98, 1.35-1.50, 1.65-1.80, 1.95-2.10, 2.20-2.35, 2.91,2.97, 3.05-3.20, 3.20-3.40, 3.55-3.70, 4.10, 4.34, 7.08-7.16, 7.32,7.80, 8.00, 8.24.

Example 3(96)2,4-difluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.43 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.60-1.75, 1.95-2.10, 2.20-2.40, 2.91,2.97, 3.05-3.20, 3.20-3.40, 3.50-3.70, 4.15, 4.34, 7.08-7.16, 7.32,7.79, 8.00, 8.24.

Example 3(97)5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-difluoro-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.33, 1.30-1.45, 1.60-1.70, 1.90-2.10, 2.15-2.30,2.91, 3.05-3.20, 3.10, 3.20-3.40, 3.50-3.60, 4.10, 4.33, 7.07-7.16,7.32, 7.79, 7.97, 8.24.

Example 3(98)2,4-difluoro-N-methyl-5-({[{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.40, 1.60-1.70, 1.95-2.05, 2.13, 2.20-2.40,2.91, 2.98, 3.05-3.20, 3.20-3.40, 3.55-3.65, 4.15, 4.34, 7.11-7.21,7.79, 8.04, 8.26.

Example 3(99)N-[4-(4-{[4-(butyl{[(1,5-dimethyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamidedihydrochloride

TLC: Rf 0.84 (chloroform:methanol=4:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.60-1.80, 1.90-2.10, 2.10-2.30, 2.27,2.95, 3.00-3.20, 3.20-3.40, 3.50-3.60, 3.92, 4.20, 4.29, 7.02-7.08,7.31, 7.51, 7.84.

Example 3(100)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzenesulfonamidedihydrochloride

TLC: Rf 0.40 (dichloromethane:methanol=5:1);

NMR (CD₃OD): δ 0.98, 1.36-1.43, 1.60-1.70, 1.98-2.02, 2.20-2.35, 2.94,3.10-3.34, 3.56-160, 4.21, 4.34, 6.90-7.01, 7.18-7.21, 7.36, 7.62, 7.89.

Example 3(101)5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-1-oxide-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.54 (chloroform:methanol=4:1);

NMR (CD₃OD): δ 0.99, 1.30-1.50, 1.55-1.70, 1.95-2.15, 2.20-2.40, 3.01,3.10-3.40, 3.55-3.70, 4.15, 4.39, 7.12-7.21, 7.25, 7.40, 7.81, 7.87,8.70.

Example 3(102)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-N-[2-(dimethylamino)ethyl]-2,4-difluorobenzamidedihydrochloride

TLC: Rf 0.17 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.80, 1.90-2.10, 2.20-2.40, 2.95,2.98, 3.00-3.20, 3.20-3.40, 3.50-3.80, 4.20, 4.29, 7.02-7.08, 7.17,7.29, 7.52, 7.91.

Example 3(103)5-{[(benzyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.51 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.97-2.06, 2.07-2.22, 2.97, 3.04-3.18, 3.47-3.58, 4.30,4.37, 4.66, 7.04-7.17, 7.21-7.45, 7.89, 8.00, 8.24.

Example 3(104) methyl4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoatehydrochloride

TLC: Rf 0.58 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.44, 1.58-1.70, 1.95-2.04, 2.12-2.30,3.08-3.18, 3.22-3.35, 3.51-3.61, 3.82, 3.91, 4.14, 4.28, 6.99, 7.09,7.14, 7.47, 7.67, 7.73, 7.85.

Example 3(105)2,4-difluoro-5-{[(hexyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.47 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.91, 1.30-1.50, 1.60-1.70, 2.00-2.10, 2.20-2.35, 2.97,3.00-3.20, 3.20-3.40, 3.50-3.70, 4.10, 4.33, 7.08-7.18, 7.32, 7.86,7.98, 8.24.

Example 3(106) methylN-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)piperidin-1-yl]methyl}phenoxy)phenyl]-N-(methylsulfonyl)glycinatehydrochloride

TLC: Rf 0.46 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.96, 1.27-1.44, 1.55-1.90, 2.10-2.20, 2.95-3.07, 3.08,3.21-3.34, 3.53, 3.74, 4.05, 4.46, 6.85-7.04, 7.03-7.45, 7.47.

Example 3(107) methylN-{4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]piperidin-1-yl}methyl)phenoxy]phenyl}-N-(methylsulfonyl)glycinatehydrochloride

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.32-1.42, 1.58-1.68, 1.70-1.97, 2.12-2.28,2.99-3.12, 3.08, 3.20-3.35, 3.57, 3.74, 4.02, 4.46, 6.92-7.04, 7.16,7.36, 7.47, 8.54.

Example 45-{[(butyl{1-[(6-{4-[(methylamino)carbonyl]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

To a solution of the compound prepared in Example 3(53) (132 mg) indimethylformamide (1 ml) was added 1-hydroxybenzotriazole (46 mg),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (65 mg)and a solution of 33% methylamine in methanol (32 μl). The reactionmixture was stirred for 2.5 hours at room temperature. To the mixturewas added a saturated aqueous solution of sodium hydrogen carbonate, andextract with ethyl acetate. The extract was dried over anhydrous sodiumsulfate, and concentrated. The obtained residue was purified by columnchromatography on silica gel (ethyl acetate:methanol=5:1). To a solutionof the obtained compound in ethyl acetate was added 4N hydrogen chloridein ethyl acetate solution. The reaction mixture was concentrated to givethe title compound (73 mg) having the following physical data.

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.32-1.45, 1.58-1.70, 1.95-2.08, 2.25-2.40, 2.92,3.10-3.22, 3.27-3.38, 3.58-3.64, 4.24, 4.37, 7.13, 7.15, 7.24, 7.86,7.90, 8.12, 8.33.

Examples 4(1)-4(9)

By the same procedure as described in Example 4 using the correspondingamine compounds instead of methylamine and the compound prepared inExample 3(53) or the compound prepared in Example 3(47), the followingcompounds of the present invention were obtained.

Example 4(1)5-({[[1-({6-[4-(aminocarbonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](butyl)amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.35-1.48, 1.59-1.70, 1.95-2.08, 2.19-2.38,3.06-3.22, 3.24-3.35, 3.55-3.65, 4.18, 4.36, 7.14, 7.16, 7.23, 7.86,7.96, 8.05, 8.30.

Example 4(2)5-{[(butyl{1-[(6-{4-[(dimethylamino)carbonyl]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.34-1.45, 1.58-1.70, 1.95-2.08, 2.20-2.40,3.02-3.22, 3.24-3.35, 3.52-3.65, 4.19, 4.36, 7.14, 7.16, 7.25, 7.52,7.86, 8.09, 8.30.

Example 4(3)5-[({butyl[1-({6-[4-(4-morpholinylcarbonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.47, 1.59-1.70, 1.95-2.08, 2.20-2.39,3.10-3.20, 3.25-3.35, 3.45-3.82, 4.18, 4.36, 7.14, 7.16, 7.25, 7.52,7.86, 8.08, 8.30.

Example 4(4)5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.35-1.47, 1.60-1.70, 1.95-2.08, 2.20-2.38,3.08-3.21, 3.25-3.40, 3.57, 3.51-3.64, 4.16, 4.36, 7.14, 7.16, 7.23,7.86, 7.90, 8.05, 8.30.

Example 4(5)5-[({butyl[1-({6-[4-({[2-(dimethylamino)ethyl]amino}carbonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.35 (dichloromethane:methanol=5:1);

NMR (CD₃OD): δ 0.97, 1.35-1.45, 1.59-1.70, 1.94-2.05, 2.23-2.40, 2.99,3.10-3.22, 3.22-3.35, 3.40, 3.55-3.65, 3.78, 4.22, 4.37, 7.14, 7.17,7.27, 7.86, 7.99, 8.13, 8.34.

Example 4(6)5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}-2,6-dimethylphenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.51 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.34-1.46, 1.57-1.68, 1.98-2.08, 2.13, 2.18-2.35,3.08-3.21, 3.22-3.40, 3.56, 3.51-3.64, 4.17, 4.33, 7.11, 7.14, 7.62,7.86, 8.06, 8.22.

Example 4(7)5-({[(1-{4-[4-(aminocarbonyl)-2-methoxyphenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.41 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.47, 1.58-1.70, 1.97-2.05, 2.12-2.31,3.04-3.18, 3.22-3.35, 3.51-3.60, 3.82, 4.15, 4.27, 6.97, 7.09, 7.14,7.47, 7.53, 7.65, 7.85.

Example 4(8)5-{[(butyl{1-[4-(2-methoxy-4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)benzyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.47, 1.58-1.70, 1.95-2.04, 2.12-2.30,3.04-3.18, 3.22-3.35, 3.50-3.61, 3.57, 3.82, 4.14, 4.27, 6.97, 7.09,7.14, 7.45, 7.47, 7.61, 7.85.

Example 4(9)5-({[butyl(1-{4-[2-methoxy-4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.44, 1.58-1.70, 1.95-2.04, 2.12-2.30,3.04-3.17, 3.22-3.35, 3.47-3.81, 3.79, 4.14, 4.27, 6.97, 7.05, 7.12,7.14, 7.20, 7.45, 7.85.

Example 5[[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl](methylsulfonyl)amino]aceticacid hydrochloride

To a solution of the compound prepared in Example 3(106) (80 mg) inmethanol (1 ml) was added 2N aqueous solution of sodium hydroxide (0.5ml). The reaction mixture was stirred for 2.5 hours at room temperature.To the reaction mixture on ice bath was added 1N hydrochloric acid untilthe pH of the solution was below 5, then it was extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate,concentrated. The obtained residue was purified by column chromatographyon silica gel (dichloromethane:methanol=9:1). To a solution of theobtained compound in ethyl acetate was added 4N hydrogen chloride inethyl acetate solution. The reaction mixture was concentrated to givethe title compound (64 mg) having the following physical data.

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.45, 1.57-1.70, 1.92-2.05, 2.12-2.31, 3.09,3.06-3.20, 3.22-3.35, 3.51-3.61, 4.17, 4.30, 4.43, 6.88-7.05, 7.06,7.12, 7.36, 7.51-7.58.

Example 5(1)[{4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}(methylsulfonyl)amino]aceticacid hydrochloride

By the same procedure as described in Example 5 using the compoundprepared in Example 3(107), the following the title compound wasobtained.

TLC: Rf 0.17 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.30-1.42, 1.57-1.70, 1.90-2.02, 2.11-2.30,2.95-3.10, 3.10, 3.23-3.40, 3.41-3.52, 4.16, 4.21, 4.30, 7.01, 7.06,7.13, 7.48, 7.57, 7.86.

Example 6(1)-6(20)

By the same procedure as described in Example 3 using the correspondingaldehyde compound instead of the compound prepared in Example 1 and thecorresponding amine compound instead of the compound prepared in Example2, the following compounds of the present invention were obtained.

Example 6(1)2-(5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorophenyl)acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.42 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.50-1.70, 1.95-2.10, 2.15-2.30, 2.97,3.05-3.20, 3.20-3.40, 3.50-3.60, 3.53, 4.10, 4.33, 7.00, 7.08-7.14,7.30-7.34, 7.97, 8.24.

Example 6(2)2-[2,4-difluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.43 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.55-1.75, 1.90-2.10, 2.15-2.35, 2.97,3.10-3.20, 3.20-3.40, 3.50-3.60, 3.53, 4.15, 4.33, 7.00, 7.08-7.14,7.30-7.34, 7.99, 8.25.

Example 6(3)5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluoro-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.41 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.98, 1.35-1.50, 1.65-1.80, 1.95-2.10, 2.20-2.35, 2.91,2.97, 3.05-3.20, 3.20-3.40, 3.55-3.70, 4.10, 4.34, 7.08-7.16, 7.32,7.80, 8.00, 8.24.

Example 6(4)2,4-difluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.43 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.60-1.75, 1.95-2.10, 2.20-2.40, 2.91,2.97, 3.05-3.20, 3.20-3.40, 3.50-3.70, 4.15, 4.34, 7.08-7.16, 7.32,7.79, 8.00, 8.24.

Example 6(5)5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-difluoro-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.33, 1.30-1.45, 1.60-1.70, 1.90-2.10, 2.15-2.30,2.91, 3.05-3.20, 3.10, 3.20-3.40, 3.50-3.60, 4.10, 4.33, 7.07-7.16,7.32, 7.79, 7.97, 8.24.

Example 6(6)2,4-difluoro-N-methyl-5-({[{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.40, 1.60-1.70, 1.95-2.05, 2.13, 2.20-2.40,2.91, 2.98, 3.05-3.20, 3.20-3.40, 3.55-3.65, 4.15, 4.34, 7.11-7.21,7.79, 8.04, 8.26.

Example 6(7)5-{[(butyl{1-[(6-{2-chloro-4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.46 (dichloromethane methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.33, 1.30-1.47, 1.59-1.70, 1.95-2.08, 2.20-2.37,3.15, 3.05-3.20, 3.22-3.35, 3.52-3.62, 4.18, 4.34, 7.10-7.28, 7.41,7.86, 8.05, 8.24.

Example 6(8)5-({[(1-{4-[4-(aminocarbonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.49, 1.59-1.70, 1.95-2.09, 2.19-2.38,3.08-3.20, 3.27-3.35, 3.51-3.65, 4.18, 4.32, 7.07, 7.08, 7.16, 7.57,7.86, 7.91.

Example 6(9)5-({[butyl(1-{4-[4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.31-1.47, 1.60-1.70, 1.98-2.07, 2.15-2.30,3.04-3.20, 3.25-3.35, 3.50-3.80, 4.13, 4.31, 7.08-7.18, 7.48, 7.54,7.86.

Example 6(10)2-{5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorophenyl}acetamidehydrochloride

TLC: Rf 0.42 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.75, 1.95-2.10, 2.10-2.30, 2.95,3.05-3.40, 3.53, 3.55-3.65, 4.15, 4.28, 7.00-7.08, 7.28, 7.29, 7.49.

Example 6(11)2-{5-[({butyl[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorophenyl}acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.44 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.15-2.30,3.05-3.40, 3.15, 3.53, 3.55-3.65, 4.15, 4.36, 7.00, 7.23, 7.33, 7.40,8.01, 8.04, 8.29.

Example 6(12)2-{5-[({butyl[1-({6-[2-chloro-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorophenyl}acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.42 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.95-2.10, 2.15-2.35,3.00-3.40, 3.30, 3.53, 3.55-3.65, 4.15, 4.37, 7.00, 7.25, 7.33, 7.35,7.53, 8.06, 8.16, 8.31.

Example 6(13)2-[5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-difluorophenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.33 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.33, 1.60-1.70, 1.90-2.10, 2.15-2.35,3.00-3.40, 3.10, 3.53, 3.55-3.65, 4.10, 4.33, 7.00, 7.07-7.13, 7.32,7.33, 7.97, 8.24.

Example 6(14)2-[2,4-difluoro-5-({[{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.12, 2.20-2.40,2.97, 3.00-3.40, 3.53, 3.55-3.65, 4.15, 4.33, 6.96-7.21, 7.33, 8.01,8.24.

Example 6(15)2-[2,4-difluoro-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.39 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.10-2.30,3.00-3.40, 3.15, 3.53, 3.55-3.65, 4.15, 4.36, 7.00, 7.22, 7.33, 7.40,8.01, 8.04, 8.29.

Example 6(16)2-[5-({[[1-({6-[2-chloro-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)-2,4-difluorophenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.44 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.94, 1.30-1.50, 1.60-1.70, 1.90-2.10, 2.10-2.30,3.00-3.40, 3.30, 3.53, 3.55-3.65, 4.10, 4.35, 7.00, 7.25, 7.33, 7.37,7.52, 8.05, 8.16, 8.31.

Example 6(17)N′(4-fluorophenyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]pyridin-3-yl}methyl)piperidin-4-yl]-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.54 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.14-2.03, 3.14, 3.12-3.25, 3.48-3.58, 4.30,4.67, 6.95, 7.16-7.25, 7.30-7.40, 7.46-7.58, 7.96, 8.00, 8.22.

Example 6(18)N-[1-({6-[2-chloro-4-(methylsulfonyl)phenoxy]pyridin-3-yl}methyl)piperidin-4-yl]-N′-(4-fluorophenyl)-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.54 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.15-2.23, 3.12-3.28, 3.31, 3.49-3.59, 4.30,4.68, 6.95, 7.10, 7.18-7.25, 7.30-7.40, 7.49-7.58, 7.98, 8.15, 8.24.

Example 6(19)N-[1-({6-[2-chloro-4-(methylsulfonyl)phenoxy]pyridin-3-yl}methyl)piperidin-4-yl]-N′-(2,4-difluorophenyl)-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.54 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.15-2.25, 3.10-3.30, 3.31, 3.50-3.60, 4.31,4.68, 6.84-6.96, 7.21, 7.30-7.39, 7.48-7.60, 7.98, 8.15, 8.24.

Example 6(20)5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}-2-methylphenoxy)pyridin-3-yl]methyl}piperidin-4-yl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.97, 1.32-1.47, 1.60-1.70, 1.97-2.04, 2.21, 2.20-2.37,3.10-3.20, 3.21-3.40, 3.57, 3.50-3.62, 4.18, 4.34, 7.10-7.20, 7.72,7.80, 7.86, 8.06, 8.26.

Example 7(1)-7(121)

By the same procedure as described in Example 3 using the correspondingaldehyde compound instead of the compound prepared in Example 1 and thecorresponding amine compound instead of the compound prepared in Example2, and it was converted into free form, if necessary, the followingcompounds of the present invention were obtained.

Example 7(1)5-({[[1-({6-[2,6-dimethyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.42 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.60-1.80, 1.95-2.10, 2.17, 2.20-2.35,3.00-3.40, 3.14, 3.50-3.70, 4.15, 4.33, 7.14, 7.21, 7.74, 7.86, 8.07,8.18.

Example 7(2)5-({[[1-({6-[2-chloro-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.48 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.93, 1.30-1.50, 1.60-1.80, 1.95-2.10, 2.20-2.40,3.10-3.40, 3.30, 3.50-3.70, 4.15, 4.37, 7.14, 7.25, 7.35, 7.53, 7.86,8.10, 8.16, 8.32.

Example 7(3)5-[({butyl[1-({6-[2-chloro-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.35 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.60-1.80, 1.95-2.10, 2.20-2.40,3.10-3.40, 3.30, 3.50-3.70, 4.15, 4.36, 7.14, 7.25, 7.35, 7.50, 7.53,7.78, 8.07, 8.16, 8.32.

Example 7(4)5-[({butyl[1-({6-[2-methyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.36 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.97, 1.30-1.50, 1.55-1.70, 1.90-2.10, 2.20-2.40, 2.26,3.00-3.40, 3.14, 3.50-3.70, 4.20, 4.35, 7.11-7.30, 7.53, 7.76-7.85,7.92, 8.07, 8.24.

Example 7(5)2,4-difluoro-5-{[(hexyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.37 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.98, 1.30-1.50, 1.60-1.70, 1.90-2.05, 2.20-2.35, 2.97,3.00-3.35, 3.50-3.70, 4.20, 4.34, 7.08-7.17, 7.32, 7.86, 8.02, 8.24.

Example 7(6)2,4-difluoro-5-{[((2-methylbenzyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.98-2.20, 2.36, 2.97, 3.04-3.18, 3.48-3.57, 4.30, 4.43,4.57, 7.04-7.33, 7.85, 7.98, 8.23.

Example 7(7)2,4-difluoro-5-({[[1-({6-[2-methyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.38 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.94, 1.30-1.50, 1.60-1.80, 1.90-2.10, 2.26, 2.20-2.40,3.05-3.40, 3.14, 3.50-3.70, 4.15, 4.33, 7.11-7.29, 7.81-7.89, 7.92,8.03, 8.23.

Example 7(8)2,4-difluoro-5-{[({1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.37 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.80, 2.20-2.30, 2.98, 3.08-3.21, 3.50-3.60, 3.83,4.34, 7.07-7.19, 7.33, 8.02, 8.27, 8.38.

Example 7(9)N′-(4-fluorophenyl)-N-[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.80, 2.12-2.22, 3.17, 3.10-3.25, 3.48-3.58, 3.79,4.27, 4.67, 6.95, 7.12, 7.22, 7.30-7.38, 7.45-7.64, 7.93, 8.12.

Example 7(10)N′-(2,4-difluorophenyl)-N-[1-({6-[2-methyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.80, 2.15-2.28, 2.24, 3.13, 3.12-3.24, 3.50-3.58,4.29, 4.68, 6.85-6.98, 7.17, 7.26, 7.34-7.38, 7.48-7.60, 7.81, 7.91,7.98, 8.17.

Example 7(11)N′-(2,4-difluorophenyl)-N-[1-({6-[2,6-dimethyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.15, 2.12-2.23, 3.13, 3.10-3.24, 3.50-3.58,4.27, 4.68, 6.85-6.98, 7.18, 7.33-7.37, 7.50-7.60, 7.73, 7.96, 8.11.

Example 7(12)N′-(2,4-difluorophenyl)-N-[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.80, 2.15-2.24, 3.17, 3.12-3.25, 3.48-3.58, 3.79,4.28, 4.68, 6.85-6.98, 7.12, 7.33-7.37, 7.50-7.60, 7.95, 8.13.

Example 7(13)2,4-difluoro-5-[({hexyl[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.35 (chloroform:methanol=7:1);

NMR (CD₃OD): δ 0.91, 1.25-1.45, 1.60-1.75, 1.90-2.10, 2.20-2.40,3.05-3.40, 3.14, 3.50-3.70, 3.81, 4.15, 4.35, 7.14, 7.15, 7.38,7.60-7.65, 7.86, 8.09, 8.24.

Example 7(14)N′-(4-fluorophenyl)-N-[1-({6-[2-methyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.75 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.63-1.80, 2.12-2.23, 2.24, 3.13, 3.10-3.25, 3.48-3.57,4.29, 4.67, 6.95, 7.15-7.35, 7.47-7.60, 7.81, 7.91, 7.97, 8.17.

Example 7(15)N-[1-({6-[2,6-dimethyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N′-(4-fluorophenyl)-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.75 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.80, 2.15, 2.10-2.23, 3.13, 3.10-3.25, 3.48-3.58,4.27, 4.67, 6.95, 7.15-7.25, 7.30-7.35, 7.48-7.60, 7.73, 7.97, 8.11.

Example 7(16)5-{[(butyl{1-[(2-methyl-6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.32-1.45, 1.58-1.70, 1.95-2.05, 2.24-2.40, 2.67,2.99, 3.20-3.35, 3.60-3.69, 4.28, 4.43, 6.95, 7.14, 7.22, 7.37, 7.87,8.20.

Example 7(17)4-chloro-2-fluoro-5-({[[1-({6-[2-methyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.94, 1.30-1.50, 1.67-1.80, 1.98-2.06, 2.26, 2.19-2.38,3.10-3.20, 3.14, 3.25-3.35, 3.55-3.65, 4.20, 4.34, 7.21, 7.28, 7.41,7.83, 7.90-7.99, 8.06, 8.24.

Example 7(18)4-chloro-5-({[[1-({6-[2,6-dimethyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)-2-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.94, 1.30-1.47, 1.65-1.80, 1.98-2.08, 2.17, 2.15-2.35,3.08-3.20, 3.13, 3.25-3.35, 3.55-3.65, 4.19, 4.33, 7.21, 7.41, 7.74,7.97, 8.06, 8.18.

Example 7(19)5-{[(butyl{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-4-chloro-2-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.54 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.35-1.48, 1.62-1.75, 1.98-2.08, 2.19-2.38, 2.97,3.08-3.20, 3.25-3.35, 3.55-3.63, 4.17, 4.34, 7.09, 7.13, 7.32, 7.42,7.94, 8.02, 8.27.

Example 7(20)5-[({butyl[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-4-chloro-2-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.54 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.99, 1.38-1.50, 1.64-1.75, 1.98-2.07, 2.20-2.38, 3.15,3.08-3.20, 3.25-3.35, 3.58-3.65, 4.18, 4.36, 7.22, 7.40, 7.41, 7.94,8.02, 8.07, 8.30.

Example 7(21)5-[({butyl[1-({6-[2-chloro-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-4-chloro-2-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.99, 1.38-1.45, 1.64-1.75, 1.98-2.07, 2.20-2.38,3.08-3.22, 3.25-3.35, 3.31, 3.58-3.65, 4.18, 4.37, 7.25, 7.36, 7.41,7.53, 7.94, 8.09, 8.16, 8.32.

Example 7(22)5-[({butyl[1-({6-[2,6-dimethyl-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-4-chloro-2-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.98, 1.35-1.48, 1.62-1.75, 1.97-2.08, 2.17, 2.19-2.38,3.08-3.21, 3.14, 3.25-3.35, 3.52-3.65, 4.19, 4.33, 7.21, 7.41, 7.73,7.94, 8.07, 8.18.

Example 7(23)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamidedihydrochloride

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.70-1.84, 2.14-2.23, 2.97, 3.20-3.35, 3.55-3.65, 4.40,4.68, 6.95, 7.17, 7.22, 7.29-7.38, 7.48-7.60, 8.19, 8.48.

Example 7(24)N-(4-{[5-({4-[[(cyclohexylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.51 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 0.93-1.15, 1.20-1.38, 1.49-1.80, 2.08-2.18, 2.97,3.10-3.21, 3.47-3.58, 4.28, 4.62, 7.07, 7.12, 7.18-7.25, 7.33,7.42-7.55, 7.98, 8.23.

Example 7(25)N-[4-({5-[(4-{phenyl[(3-thienylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.80, 2.12-2.20, 2.98, 3.12-3.26, 3.50-3.59, 4.32,4.68, 6.91, 7.10, 7.04-7.20, 7.27-7.37, 7.48-7.60, 8.07, 8.31.

Example 7(26)N-(4-{[5-({4-[(anilinocarbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.15-2.24, 2.97, 3.12-3.23, 3.49-3.57, 4.27,4.68, 6.97-7.14, 7.18-7.22, 7.28-7.38, 7.48-7.60, 7.89, 8.17.

Example 7(27)N-(4-{[5-({4-[[(benzylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.60-1.78, 2.08-2.18, 2.97, 3.08-3.21, 3.48-3.55, 4.25,4.29, 4.64, 7.08, 7.10-7.27, 7.32, 7.40-7.58, 8.01, 8.27.

Example 7(28)N-{4-[(5-{[4-(phenyl{[(2-phenylethyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.57-1.73, 2.04-2.13, 2.67, 2.98, 3.10-3.22, 3.27-3.35,3.48-3.55, 4.31, 4.60, 7.04-7.25, 7.34, 7.40-7.47, 8.06, 8.31.

Example 7(29)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.30 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.20, 2.97, 3.10-3.25, 3.50-3.60, 4.29,4.65, 6.93-7.13, 7.22-7.33, 7.53, 7.61, 7.94, 8.21.

Example 7(30)N-[4-({5-[(4-{3-thienyl[(3-thienylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.55 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.78, 2.11-2.20, 2.97, 3.12-3.25, 3.48-3.58, 4.28,4.67, 6.95, 7.00, 7.06, 7.11, 7.17-7.23, 7.31, 7.49, 7.60, 7.90, 8.18.

Example 7(31)N-(4-{[5-({4-[{[(3-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.12-2.24, 2.97, 3.12-3.25, 3.48-3.58, 4.27,4.68, 6.72, 6.93, 7.03-7.35, 7.48-7.60, 7.89, 8.17.

Example 7(32)N-(4-{[5-({4-[{[(2-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.56 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.63-1.80, 2.18-2.25, 2.97, 3.12-3.25, 3.48-3.58, 4.28,4.69, 6.98-7.15, 7.31, 7.35-7.40, 7.50-7.62, 7.73, 7.90, 8.17.

Example 7(33)N-(4-{[5-({4-[{[(4-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.13-2.21, 2.97, 3.12-3.25, 3.48-3.57, 3.73,4.27, 4.67, 6.79, 7.05, 7.09, 7.10, 7.28-7.35, 7.47-7.58, 7.90, 8.17.

Example 7(34)N-(4-{[5-({4-[{[(3-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.13-2.25, 2.97, 3.12-3.25, 3.48-3.57, 3.72,4.28, 4.67, 6.58, 6.73, 6.94, 7.04-7.15, 7.29-7.35, 7.49-7.60, 7.90,8.18.

Example 7(35)N-(4-{[5-({4-[{[(2-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.15-2.27, 2.97, 3.12-3.25, 3.50-3.60, 3.55,4.29, 4.71, 6.80-6.97, 7.05, 7.11, 7.31, 7.37, 7.51-7.64, 7.91, 7.95,8.18.

Example 7(36)N-(4-{[5-({4-[{[(4-methylphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

Amorphous powder;

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.34-1.50, 1.80-1.91, 2.10-2.20, 2.23, 2.83-2.98, 2.95,3.44, 4.43, 6.88, 6.98-7.10, 7.28, 7.45-7.57, 7.73, 7.98.

Example 7(37)N-(4-{[5-({4-[{[(3-methylphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.35-1.50, 1.80-1.91, 2.08-2.20, 2.24, 2.84-2.98, 2.94,3.44, 4.43, 6.80, 6.87, 6.97-7.12, 7.26-7.34, 7.44-7.58, 7.73, 7.98.

Example 7(38)N-(4-{[5-({4-[{[(2-methylphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.38-1.54, 1.84-1.96, 1.91, 2.10-2.20, 2.85-2.98, 2.95,3.44, 4.43, 6.88, 6.97, 7.02-7.14, 7.28, 7.35, 7.42-7.60, 7.73, 7.98.

Example 7(39)N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

White amorphous powder;

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.32-1.48, 1.80-1.89, 2.08-2.20, 2.82-2.90, 3.01, 3.40,4.53, 5.83, 6.43, 6.85, 7.08-7.28, 7.44-7.55, 7.61, 8.00.

Example 7(40)N-(4-{[5-({4-[{[(3-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.32-1.50, 1.80-1.90, 2.08-2.20, 2.82-2.90, 3.01, 3.41,4.53, 5.85, 6.52, 6.85, 6.94, 7.02-7.15, 7.19-7.28, 7.35, 7.44-7.55,7.61, 8.01.

Example 7(41)N-(4-{[5-({4-[{[(2-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.38-1.53, 1.82-1.90, 2.08-2.20, 2.83-2.92, 3.01, 3.41,4.53, 6.47, 6.59, 6.85, 6.87, 7.12, 7.18, 7.22-7.28, 7.42-7.55, 7.61,8.01, 8.27.

Example 7(42)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(1-methyl-1H-pyrazol-4-yl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.30-1.48, 1.70-1.80, 2.08-2.19, 2.81-2.90, 3.01, 3.41,3.96, 4.46, 6.26, 6.35, 6.85, 6.92, 7.11, 7.18-7.28, 7.37, 7.61, 8.01.

Example 7(43)2-fluoro-5-({[{1-[6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide

Free form;

White amorphous powder;

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.32-1.48, 1.80-1.90, 2.08-2.20, 2.81-2.92, 3.00, 3.40,4.55, 5.86, 5.97, 6.62-6.77, 6.85, 7.06, 7.11, 7.18-7.30, 7.34,7.45-7.55, 7.61, 8.00, 8.04.

Hydrochloride (or dihydro chloride);

White amorphous powder;

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.81, 2.12-2.23, 2.97, 3.12-3.35, 3.47-3.58, 4.29,4.67, 7.07-7.16, 7.29-7.36, 7.43, 7.48-7.58, 7.68, 7.95, 8.22.

Example 7(44)4-fluoro-N-{1-[6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}-N-phenylbenzamide

TLC: Rf 0.58 (chloroform:methanol=7:1);

NMR (CDCl₃): δ 1.50-1.70, 1.85-1.95, 2.10-2.30, 2.85-2.95, 2.98, 3.41,4.72, 6.75-6.84, 6.95-6.98, 7.07, 7.19-7.25, 7.59, 7.99.

Example 7(45)N-[4-({5-[(4-{phenyl[(3-pyridinylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide

TLC: Rf 0.40 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.34-1.50, 1.80-1.90, 2.10-2.20, 2.80-2.90, 3.00, 3.40,4.54, 5.87, 6.83, 7.09, 7.18, 7.20-7.28, 7.45-7.55, 7.59, 7.91, 7.99,8.16, 8.20.

Example 7(46)N-(4-{[5-({4-[(aminocarbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.38 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.30-1.44, 1.76-1.85, 2.08-2.18, 2.80-2.88, 3.01, 3.39,4.20, 4.48, 6.83, 6.90, 7.11, 7.13-7.18, 7.22-7.28, 7.35-7.45, 7.59,7.98.

Example 7(47)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(4-methoxyphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.43 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.31-1.49, 1.77-1.86, 2.09-2.18, 2.81-2.90, 3.01, 3.40,3.86, 4.50, 5.85, 6.38, 6.84, 6.89, 6.96, 7.08-7.25, 7.60, 7.99.

Example 7(48)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(3-methoxyphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.43 (dichloromethane:methanol=9:1);

NMR (CDCl₃): δ 1.37-1.51, 1.80-1.89, 2.08-2.18, 2.81-2.90, 3.01, 3.40,3.83, 4.51, 5.87, 6.38, 6.73, 6.80, 6.84, 6.90, 6.98, 7.08-7.26, 7.37,7.60, 8.00.

Example 7(49)N-(4-{[5-({3-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.29 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.90-2.05, 2.20-2.30, 2.35-2.50, 2.60-2.75, 2.97,3.85-3.95, 4.16, 4.55, 6.92-6.98, 7.06-7.14, 7.19-7.24, 7.29-7.33,7.36-7.40, 7.48-7.58, 8.01, 8.25.

Example 7(50)4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}benzoicacid hydrochloride (or dihydrochloride)

TLC: Rf 0.39 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.80, 2.10-2.25, 3.10-3.30, 3.50-3.60, 4.30, 4.65,6.92-6.98, 7.13, 7.19-7.24, 7.31-7.34, 7.49-7.55, 7.96, 8.08, 8.25.

Example 7(51)N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.63 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.80, 2.10-2.30, 2.98, 3.10-3.30, 3.50-3.60, 4.31,4.70, 6.88-6.92, 7.09, 7.15, 7.32-7.34, 7.33, 7.51-7.58, 8.04, 8.29.

Example 7(52)N-(4-{[5-({4-[{[(3-fluoro-4-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane methanol=9:1);

NMR (CD₃OD): δ 1.65-1.82, 2.12-2.22, 2.98, 3.12-3.28, 3.48-3.58, 3.79,4.32, 4.67, 6.84-6.96, 7.09, 7.13-7.22, 7.28-7.38, 7.45-7.58, 8.05,8.30.

Example 7(53)N-(4-{[5-({4-[{[(3-chloro-4-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.82, 2.12-2.22, 2.98, 3.12-3.28, 3.48-3.58, 3.81,4.32, 4.68, 6.92, 7.06, 7.09, 7.16, 7.30-7.38, 7.45-7.58, 8.05, 8.30.

Example 7(54)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidedihydrochloride (or trihydrochloride)

Amorphous powder;

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.85, 2.12-2.25, 2.68, 2.97, 3.15-3.28, 3.50-3.60,4.31, 4.71, 7.07, 7.13, 7.29-7.38, 7.50-7.62, 7.73, 8.01, 8.25, 8.31,8.97.

Example 7(55)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acetamidehydrochloride (or ihydrochloride)

Amorphous powder;

TLC: Rf 0.23 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.25, 3.10-3.25, 3.50-3.60, 3.55, 4.28,4.70, 6.95, 7.04-7.10, 7.19-7.24, 7.31-7.38, 7.49-7.55, 7.93, 8.21.

Example 7(56)N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]phenyl}methanesulfonamidedihydrochloride

TLC: Rf 0.21 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.70-1.85, 2.10-2.25, 2.31, 2.33, 3.03, 3.20-3.35,3.55-3.65, 4.20, 4.70, 6.96, 7.21-7.25, 7.33-7.41, 7.50-7.56.

Example 7(57)4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]-N-[2-(4-morpholinyl)ethyl]benzenesulfonamidetrihydrochloride

TLC: Rf 0.20 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.70-1.85, 2.10-2.25, 2.34, 2.41, 3.20-3.40, 3.50-3.65,3.80-3.95, 4.00-4.15, 4.21, 4.70, 6.96, 7.20-7.25, 7.35, 7.45-7.56,7.75, 8.05.

Example 7(58)N-{4-[(5-{[4-((3,5-dimethyl-4-isoxazolyl){[(4-fluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.88, 2.09-2.23, 2.20, 2.40, 2.97, 3.12-3.25,3.50-3.60, 4.32, 4.60, 6.99, 7.09, 7.13, 7.25-7.35, 8.01, 8.25.

Example 7(59)N-{4-[(5-{[4-(1,3-benzothiazol-6-yl{[(4-fluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.85, 2.19-2.28, 2.97, 3.12-3.25, 3.50-3.60, 4.30,4.71, 6.94, 7.07, 7.13, 7.23, 7.32, 7.51, 8.00, 8.15, 8.20, 8.25, 9.46.

Example 7(60)N-(4-{[5-({4-[{[(3,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.51 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.81, 2.12-2.22, 2.97, 3.12-3.25, 3.48-3.58, 4.29,4.68, 6.93, 7.02-7.15, 7.28-7.35, 7.38, 7.45-7.58, 7.95, 8.21.

Example 7(61)N-(4-{[5-({4-[[(2,3-dihydro-1,4-benzodioxin-6-ylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.51 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.63-1.80, 2.12-2.22, 2.97, 3.11-3.25, 3.48-3.55, 4.17,4.29, 4.68, 6.56, 6.66, 6.81, 7.07, 7.12, 7.27-7.35, 7.45-7.58, 7.96,8.22.

Example 7(62)N-(4-{[5-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.63-1.80, 2.12-2.22, 2.97, 3.12-3.25, 3.48-3.58, 4.28,4.68, 6.85-6.98, 7.03-7.08, 7.11, 7.31, 7.53-7.60, 7.64, 7.89, 8.18.

Example 7(63)N-(4-{[5-({4-[{[(3,4-difluorophenyl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.80, 2.10-2.20, 2.97, 3.12-3.25, 3.48-3.58, 4.28,4.68, 6.94-7.16, 7.31, 7.40, 7.51, 7.61, 7.90, 8.18.

Example 7(64)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(2-methoxyphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.61-1.83, 2.15-2.25, 2.97, 3.10-3.22, 3.48-3.56, 3.84,4.28, 4.58, 6.95, 7.05-7.29, 7.32, 7.46, 7.97, 8.23.

Example 7(65)N-{4-[(5-{[4-((4-fluorophenyl){[(4-fluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.60-1.78, 2.12-2.21, 2.97, 3.10-3.25, 3.48-3.58, 4.28,4.65, 6.95, 7.05, 7.09, 7.19-7.37, 7.90, 8.17.

Example 7(66)N-{4-[(5-{[4-((3-fluorophenyl){[(4-fluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.85, 2.12-2.25, 2.97, 3.12-3.25, 3.48-3.58, 4.28,4.65, 6.95, 7.04-7.20, 7.22-7.33, 7.30, 7.53, 7.90, 8.17.

Example 7(67)N′-(4-chlorophenyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylureahydrochloride (or dihydrochloride)

TLC: Rf 0.26 (ethyl acetate);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 3.10-3.30, 3.14, 3.50-3.60, 4.30,4.65, 7.17-7.23, 7.31-7.39, 7.52-7.55, 7.90-8.02, 8.21.

Example 7(68)N′-(4-fluorophenyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-(3-thienyl)ureahydrochloride (or dihydrochloride)

TLC: Rf 0.29 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.05-2.20, 3.14, 3.15-3.25, 3.50-3.60, 4.29,4.65, 6.97, 7.04, 7.18-7.27, 7.38, 7.52, 7.61, 7.96-8.02, 8.23.

Example 7(69)2-chloro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.81, 2.12-2.22, 2.86, 2.97, 3.12-3.25, 3.49-3.58,4.29, 4.67, 7.07, 7.13, 7.25-7.35, 7.43, 7.46-7.60, 7.96, 8.22.

Example 7(70)2-chloro-N,N-dimethyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.81, 2.12-2.22, 2.86, 2.97, 3.08, 3.12-3.25,3.49-3.58, 4.30, 4.67, 7.08, 7.14, 7.27-7.36, 7.48-7.60, 7.99, 8.25.

Example 7(71)N-(4-{[5-({4-[{[(4-chloro-3-nitrophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC: Rf 0.39 (chloroform:methanol=7:1);

NMR (CDCl₃): δ 1.40-1.60, 1.80-1.90, 2.10-2.20, 2.80-2.90, 2.99, 3.46,4.51, 4.64, 6.08, 6.84, 7.09, 7.21-7.27, 7.31-7.41, 7.51-7.54, 7.61,7.89, 8.01.

Example 7(72)N-(4-{[5-({4-[({[4-(methylsulfonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.85, 2.10-2.30, 2.97, 3.05, 3.10-3.30, 3.50-3.60,4.29, 4.70, 7.06, 7.11, 7.30-7.35, 7.32, 7.51-7.58, 7.77, 7.94, 8.20.

Example 7(73)N-(4-{[5-({4-[({[3-(methylsulfonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.49 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.85, 2.10-2.25, 2.98, 3.07, 3.10-3.30, 3.50-3.60,4.31, 4.70, 7.08, 7.15, 7.31-7.36, 7.44-7.59, 8.02, 8.02, 8.26.

Example 7(74)2-chloro-5-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamidehydrochloride

TLC: Rf 0.43 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.79, 2.12-2.22, 2.95, 3.10-3.22, 3.45-3.55, 4.22,4.67, 7.01, 7.02, 7.25-7.34, 7.41, 7.46-7.58.

Example 7(75)N-(4-{[5-({4-[({[4-chloro-3-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.43 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.82, 2.12-2.22, 2.98, 3.14-3.35, 3.49-3.80, 4.31,4.67, 7.08, 7.14, 7.28-7.37, 7.45-7.59, 8.02, 8.27.

Example 7(76)2-chloro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzoicacid hydrochloride (or dihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=5:1);

NMR (CD₃OD): δ 1.64-1.82, 2.12-2.25, 2.97, 3.12-3.24, 3.47-3.60, 4.29,4.67, 7.06, 7.11, 7.28-7.36, 7.41, 7.45-7.60, 7.82, 7.94, 8.20.

Example 7(77)N′-(4-chloro-3-nitrophenyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylurea

TLC: Rf 0.50 (ethyl acetate);

NMR (CDCl₃): δ 1.35-1.55, 1.80-1.90, 2.10-2.25, 2.90-3.00, 3.06, 3.44,4.50, 6.04, 6.93, 7.20-7.39, 7.31-7.41, 7.50-7.53, 7.67, 7.92-8.05.

Example 7(78)2-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamidehydrochloride

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.62-1.79, 2.12-2.21, 2.99, 3.08-3.22, 3.43-3.57, 4.23,4.67, 6.95, 7.01, 7.06, 7.22, 7.29-7.35, 7.32-7.59, 7.70.

Example 7(79)2-fluoro-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.81, 2.13-2.25, 3.14, 3.10-3.25, 3.50-3.58, 4.31,4.67, 7.08, 7.19, 7.30-7.58, 7.69, 7.95-8.04, 8.23.

Example 7(80)2-fluoro-5-{[((3-fluorophenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.85, 2.14-2.23, 2.97, 3.12-3.25, 3.50-3.58, 4.30,4.65, 7.04-7.19, 7.25, 7.31, 7.46, 7.51, 7.70, 7.92, 8.23.

Example 7(81)2-fluoro-5-[({(3-fluorophenyl)[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.87, 2.15-2.25, 3.14, 3.12-3.25, 3.50-3.58, 4.31,4.67, 7.09, 7.12-7.20, 7.25, 7.37, 7.46, 7.54, 7.71, 7.90-8.04, 8.23.

Example 7(82)2-fluoro-5-[({(3-fluorophenyl)[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.67-1.85, 2.15-2.25, 3.17, 3.12-3.25, 3.48-3.58, 3.80,4.28, 4.65, 7.04-7.19, 7.25, 7.35, 7.46, 7.50-7.65, 7.71, 7.95, 8.13.

Example 7(83)N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

White amorphous powder;

TLC: Rf 0.36 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 2.12, 2.97, 3.10-3.25, 3.45-3.55,4.27, 4.65, 7.00-7.12, 7.30-7.33, 7.49-7.55, 7.78, 7.90, 8.18.

Example 7(84)N-[2-fluoro-5-({[{1-[(6-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.31 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 2.12, 2.99, 3.10-3.25, 3.45-3.55,3.69, 4.26, 4.65, 6.87, 6.98-7.08, 7.06, 7.31-7.34, 7.49-7.55, 7.78,7.86, 8.11.

Example 7(85)N-[2-fluoro-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.53 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 2.12, 3.10-3.25, 3.14, 3.45-3.55,4.30, 4.65, 7.00-7.05, 7.19, 7.31-7.39, 7.50-7.55, 7.90, 7.94-8.02,8.11.

Example 7(86)N-[2-fluoro-5-({[[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.52 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 2.12, 3.10-3.25, 3.17, 3.45-3.55,3.79, 4.26, 4.66, 7.00-7.11, 7.19, 7.31-7.36, 7.49-7.63, 7.78, 7.78,8.11.

Example 7(87)2-fluoro-5-{[((3-fluorophenyl){1-[(6-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.69-1.85, 2.12-2.25, 3.00, 3.12-3.25, 3.48-3.58, 3.70,4.28, 4.65, 6.87, 6.99-7.19, 7.25, 7.46, 7.54, 7.71, 7.93, 8.17.

Example 7(88)2-fluoro-5-({[{1-[(6-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.81, 2.12-2.24, 3.00, 3.12-3.25, 3.48-3.58, 3.70,4.28, 4.67, 6.87, 7.00-7.12, 7.29-7.35, 7.42, 7.47-7.58, 7.68, 7.94,8.18.

Example 7(89)2-fluoro-5-({[[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.64-1.80, 2.12-2.22, 3.17, 3.12-3.25, 3.48-3.58, 3.79,4.28, 4.67, 7.04-7.14, 7.29-7.38, 7.43, 7.48-7.64, 7.68, 7.94, 8.13.

Example 7(90)N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidedihydrochloride (or trihydrochloride)

White amorphous powder;

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.70-1.90, 2.12-2.25, 2.68, 2.97, 3.12-3.35, 3.48-3.60,4.33, 4.70, 7.08, 7.12-7.23, 7.25-7.35, 7.55, 7.73, 8.05, 8.23-8.34,8.96.

Example 7(91)N-(3-fluorophenyl)-N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]ureadihydrochloride (or trihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.70-1.90, 2.12-2.25, 2.68, 3.14, 3.12-3.35, 3.48-3.60,4.33, 4.70, 7.12-7.21, 7.29, 7.38, 7.56, 7.73, 8.00, 8.03, 8.22-8.36,8.96.

Example 7(92)N-(3-fluorophenyl)-N-[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N′-(6-methyl-3-pyridinyl)ureadihydrochloride (or trihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.70-1.90, 2.12-2.25, 2.68, 3.17, 3.12-3.35, 3.48-3.60,3.80, 4.30, 4.70, 7.12, 7.15-7.23, 7.29, 7.35, 7.51-7.64, 7.73, 7.99,8.15, 8.31, 8.96.

Example 7(93)N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.33 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 2.97, 2.97, 3.10-3.25, 3.40-3.60,4.27, 4.65, 7.03-7.11, 7.29-7.33, 7.44-7.54, 7.87, 8.16.

Example 7(94)N-[2-fluoro-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.41 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 2.97, 3.14, 3.15-3.25, 3.45-3.55,4.30, 4.62, 7.03-7.06, 7.18, 7.31-7.39, 7.44-7.54, 7.95-8.02, 8.22.

Example 7(95)N-[2-fluoro-5-({[[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]methanesulfonamidehydrochloride (or dihydrochloride)

TLC: Rf 0.39 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.25, 2.97, 3.10-3.25, 3.17, 3.45-3.55,3.79, 4.26, 4.65, 7.03-7.06, 7.12, 7.31-7.36, 7.45-7.63, 7.91, 8.10.

Example 7(96)2-[4-({4-[[({4-fluoro-3-[(methylsulfonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamidehydrochloride

TLC: Rf 0.20 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.30, 2.97, 2.99, 3.10-3.20, 3.45-3.55,4.23, 4.65, 6.99-7.04, 7.31-7.55, 7.69.

Example 7(97)2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.81, 2.12-2.23, 2.89, 2.97, 3.12-3.25, 3.48-3.58,4.29, 4.67, 7.01-7.15, 7.27-7.35, 7.40, 7.47-7.57, 7.61, 7.95, 8.21.

Example 7(98)2-fluoro-N-methyl-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.50 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.81, 2.12-2.23, 2.89, 3.14, 3.12-3.25, 3.48-3.59,4.30, 4.67, 7.06, 7.18, 7.30-7.43, 7.47-7.57, 7.61, 7.94-8.05, 8.22.

Example 7(99)N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylureadihydrochloride (or trihydrochloride)

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.70-1.87, 2.12-2.24, 2.68, 3.14, 3.17-3.35, 3.50-3.60,4.33, 4.71, 7.18, 7.32-7.36, 7.38, 7.42-7.59, 7.72, 8.00, 8.05, 8.27,8.30, 8.96.

Example 7(100)2-[4-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamidehydrochloride

TLC: Rf 0.43 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.61-1.80, 2.12, 2.05-2.22, 2.99, 3.05-3.21, 3.45-3.55,4.23, 4.67, 697-7.08, 7.28-7.35, 7.35-7.58, 7.69, 7.77.

Example 7(101)N-(3-methyl-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.85, 2.11, 2.12-2.23, 2.67, 2.97, 3.12-3.28,3.50-3.60, 4.30, 4.71, 7.02, 7.04, 7.15, 7.20, 7.31-7.38, 7.49-7.60,7.73, 8.00, 8.17, 8.22, 8.31, 8.96.

Example 7(102)N-(3-chloro-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.85, 2.12-2.25, 2.67, 3.01, 3.15-3.28, 3.48-3.58,4.30, 4.72, 7.12, 7.19-7.28, 7.31-7.37, 7.41, 7.48-7.60, 7.74, 7.98,8.17, 8.30, 8.97.

Example 7(103)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)ethanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.32, 1.70-1.85, 2.15-2.25, 2.68, 3.11, 3.15-3.28,3.50-3.60, 4.33, 4.71, 7.08, 7.14, 7.30-7.38, 7.50-7.60, 7.73, 8.07,8.28-8.35, 8.96.

Example 7(104)N-{4-[(5-{[4-((3-methylphenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.87, 2.12-2.23, 2.41, 2.68, 2.97, 3.13-3.28,3.50-3.60, 4.31, 4.71, 7.05-7.18, 7.29-7.37, 7.43, 7.73, 8.01, 8.13,8.26, 8.31, 8.96.

Example 7(105)2-fluoro-5-{[((3-methylphenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.46 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.81, 2.12-2.24, 2.40, 2.97, 3.13-3.28, 3.48-3.58,4.29, 4.67, 7.04-7.17, 7.28-7.35, 7.37-7.47, 7.68, 7.95, 8.21.

Example 7(106)2-fluoro-N-methyl-5-{[((3-methylphenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.65-1.81, 2.12-2.22, 2.40, 2.89, 2.97, 3.12-3.26,3.48-3.58, 4.30, 4.67, 7.02-7.18, 7.28-7.35, 7.36-7.44, 7.61, 7.99,8.25.

Example 7(107)N-(2-fluoro-5-{[((3-methylphenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.25, 2.12, 2.40, 2.97, 3.10-3.30,3.50-3.60, 4.27, 4.65, 7.00-7.15, 7.30, 7.31, 7.42, 7.78, 7.90, 8.17.

Example 7(108)N-(2-fluoro-5-{[((3-fluorophenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.46 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.25, 2.13, 2.97, 3.10-3.30, 3.50-3.60,4.28, 4.65, 6.98-7.17, 7.29, 7.31, 7.54, 7.82, 7.94, 8.20.

Example 7(109)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamidetrihydrochloride

TLC: Rf 0.49 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.71-1.88, 2.15-2.26, 2.68, 2.97, 3.22-3.35, 3.58-3.68,4.42, 4.75, 7.17, 7.29-7.38, 7.52-7.62, 7.73, 8.17, 8.20, 8.31, 8.48,8.97.

Example 7(110)2-fluoro-5-{[((3-fluorophenyl){1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-N-methylbenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.45 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.70-1.85, 2.15-2.23, 2.89, 2.97, 3.12-3.25, 3.50-3.58,4.30, 4.65, 7.03-7.19, 7.25, 7.32, 7.42, 7.54, 7.65, 7.99, 8.25.

Example 7(111)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-azepanyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.42 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.70-2.50, 2.67, 2.98, 3.18-3.35, 3.40-3.62, 4.37, 4.50,7.10, 7.16, 7.30-7.40, 7.48-7.60, 7.72, 8.12, 8.29, 8.33, 8.96.

Example 7(112)N-(4-{[5-({(3R)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 2.40, 2.65, 2.69, 2.98, 141-3.65, 3.80-3.98, 4.30-4.72,7.08-7.20, 7.28-7.62, 7.74, 8.14, 8.32, 8.39, 8.51, 8.97.

Example 7(113)N-(4-{[5-({(3S)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 2.40, 2.65, 2.69, 2.98, 3.41-3.65, 3.80-3.98, 4.30-4.72,7.08-7.20, 7.28-7.62, 7.74, 8.14, 8.32, 8.39, 8.51, 8.97.

Example 7(114)N-(2-fluoro-5-{[((3-fluorophenyl){1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.29 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.90, 2.00-2.20, 2.11, 2.12, 2.97, 3.10-3.30,3.50-3.60, 4.27, 4.63, 6.98-7.06, 7.13-7.27, 7.53, 7.81, 7.94, 8.17.

Example 7(115)N-[5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-fluorophenyl)amino]carbonyl}amino)-2-fluorophenyl]acetamidehydrochloride (or dihydrochloride)

TLC: Rf 0.24 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.32, 1.60-1.80, 2.10-2.30, 2.12, 3.08, 3.10-3.25,3.50-3.60, 4.29, 4.70, 7.00-7.16, 7.25, 7.31, 7.54, 7.81, 7.95, 8.22.

Example 7(116)2-fluoro-5-({[{1-[(6-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.68-1.82, 2.12, 2.09-2.22, 2.98, 3.12-3.25, 3.48-3.59,4.31, 4.68, 7.01-7.23, 7.30-7.37, 7.43, 7.47-7.58, 7.68, 8.03, 8.27.

Example 7(117)5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)-2-fluorobenzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.48 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.32, 1.65-1.82, 2.12-2.22, 3.10, 3.10-3.25, 3.49-3.58,4.31, 4.68, 7.05-7.10, 7.13, 7.29-7.36, 7.43, 7.47-7.58, 7.68, 8.02,8.28.

Example 7(118)N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}ethanesulfonamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.46 (dichloromethane:methanol=9:1);

NMR (CD₃OD): δ 1.32, 1.72-1.90, 2.12-2.25, 2.68, 3.11, 3.18-3.30,3.50-3.60, 4.34, 4.70, 7.07-7.23, 7.29, 7.33, 7.56, 7.74, 8.10,8.29-8.38, 8.97.

Example 7(119)2-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]benzamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.69 (chloroform:methanol=5:1);

NMR (CD₃OD): δ 1.70-1.90, 2.10-2.30, 2.68, 2.93, 3.20-3.40, 3.50-3.60,4.41, 4.70, 7.04, 7.33-7.43, 7.50-7.60, 7.73, 7.96, 8.17, 8.27, 8.30,8.54, 8.96.

Example 7(120)2-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-[(methylsulfonyl)amino]benzamidedihydrochloride (or trihydrochloride)

TLC: Rf 0.59 (chloroform:methanol=5:1);

NMR (CD₃OD): δ 1.70-1.90, 2.10-2.30, 2.68, 2.93, 3.20-3.40, 3.50-3.70,4.41, 4.70, 7.03, 7.15-7.20, 7.30, 7.41, 7.56, 7.74, 7.96, 8.25-8.35,8.39, 8.54, 8.97.

Example 7(121)2-{[5-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(3-fluorophenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]benzamidehydrochloride (or dihydrochloride)

TLC: Rf 0.56 (chloroform:methanol=5:1);

NMR (CD₃OD): δ 1.70-1.90, 2.10-2.30, 2.12, 2.93, 3.20-3.40, 3.50-3.70,4.37, 4.65, 6.99-7.10, 7.03, 7.15-7.20, 7.25, 7.40, 7.54, 7.82, 7.96,8.15, 8.28, 8.49.

Example 84-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-N-(2-methoxyethyl)benzamidehydrochloride (or dihydrochloride)

To a solution of the compound prepared in Example 7(50) (80 mg) inN,N-dimethylformamide (3 ml) was added0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (84 mg), diisopropylethylamine (38 μl) and1-methoxyethylamine (19 μl), and stirred overnight. To the reactionmixture was added a saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, concentrated. The obtained residue wastreated with 4N hydrogen chloride in ethyl acetate solution to give thetitle compound (65 mg) having the following physical data.

TLC: Rf 0.49 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.80, 2.10-2.25, 3.10-3.30, 3.30-3.40, 3.50-3.60,3.56, 4.29, 4.70, 6.92-6.98, 7.11, 7.19-7.24, 7.31-7.34, 7.52-7.55,7.89, 7.90, 8.20.

Example 8(1)N′-(4-fluorophenyl)-N-[1-({6-[4-(4-morpholinylcarbonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylureahydrochloride (or dihydrochloride)

By the same procedure as described in Example 8 using morpholine insteadof 1-methoxyethylamine the following the title compound having thefollowing physical data was obtained.

TLC: Rf 0.51 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.80, 2.10-2.25, 3.10-3.25, 3.40-3.55, 3.55-3.80,4.26, 4.65, 6.92-6.95, 7.11, 7.19-7.23, 7.32-7.34, 7.49-7.55, 7.94,8.18.

Example 9N-(4-{[5-({4-[{[(3-amino-4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamidedihydrochloride (or trihydrochloride)

To a solution of the compound prepared in Example 7(71) (720 mg) inacetic acid (10 ml) and water (10 ml) was added iron powder (244 mg),and the mixture was stirred for 2 hours at 40° C. The reaction mixturewas filtrated through Celite (registered trademark). After the filtratewas neutralized with 1N aqueous solution of sodium hydroxide, it wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous sodium sulfate, and concentrated. Theobtained residue was purified by column chromatography on silica gel(dichloromethane:methanol=20:1). To this free form treated with 4Nhydrogen chloride in ethyl acetate solution to give the title compound(420 mg) having the following physical data.

TLC: Rf 0.48 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.80, 2.10-2.30, 2.97, 3.10-3.25, 3.50-3.60, 4.28,4.70, 7.05, 7.10, 7.15, 7.29-7.32, 7.30, 7.37, 7.50-7.55, 7.72, 7.90,8.17.

Example 10N-[2-chloro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]methanesulfonamidehydrochloride (or dihydrochloride)

To mixture of the free form compound prepared in Example 9 (160 mg) andtriethylamine (36 μl) in tetrahydrofuran (5 ml) was addedmethanesulfonyl chloride (20 μl), and the mixture was stirred overnightat room temperature. The reaction mixture was extracted with ethylacetate, dried over anhydrous sodium sulfate, and concentrated. Theobtained residue was dissolved in tetrahydrofuran (10 ml), and to thissolution was added tetrabutylammonium fluoride (146 μl). The mixture wasstirred for 3 hours at 60° C. To the mixture was added water, extractedwith ethyl acetate. The organic layer was washed with water and brine,dried over anhydrous sodium sulfate, and concentrated. The obtainedresidue was purified by column chromatography on silica gel(dichloromethane:methanol=20:1). The obtained compound was treated with4N hydrogen chloride in ethyl acetate solution to give the titlecompound (35 mg) having the following physical data.

TLC: Rf 0.48 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.80, 2.10-2.25, 2.97, 2.97, 3.10-3.25, 3.50-3.60,4.29, 4.70, 7.06, 7.10-7.15, 7.28-7.34, 7.52-7.58, 7.94, 8.21.

Example 11N-[2-chloro-5-({[{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

To a solution of the free form compound prepared in Example 9 (160 mg)in pyridine (4 ml) was added acetic acid anhydride (72.4 μl), and themixture was stirred overnight at room temperature. The reaction mixturewas extracted with ethyl acetate, dried over anhydrous sodium sulfate,and concentrated. To a solution of the obtained residue in methanol (4ml) was added 28% sodium methoxde in methanol solution (506 μl), stirredfor 30 minutes at room temperature. The reaction mixture wasconcentrated, added water, and extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated. The obtained residue was treated with 4Nhydrogen chloride in ethyl acetate solution to give the title compound(64 mg) having the following physical data.

TLC: Rf 0.40 (chloroform:methanol=10:1);

NMR (CD₃OD): δ 1.65-1.80, 2.13, 2.15-2.25, 2.97, 3.10-3.35, 3.50-3.60,4.30, 4.65, 7.07, 7.12-7.16, 7.25-7.34, 7.49-7.51, 7.68, 7.99, 8.25.

Example 12N-[2-chloro-5-({[[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]phenyl)amino]carbonyl}amino)phenyl]acetamidehydrochloride (or dihydrochloride)

To a solution of amine compound prepared by the reduction whichprocedure was described in Example 9 using the compound prepared inExample 7(77) (160 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (34 μl) intetrahydrofuran (5 ml) was added acetic acid anhydride (63 μl), and themixture was refluxed for 4 hours. The reaction mixture was poured intowater, and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated. To a solution of the obtained residue in methanol (4 ml)was added 28% sodium methoxde in methanol solution (447 μl), stirred for30 minutes at room temperature. The reaction mixture was concentrated,added water, and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over anhydrous sodium sulfate, andconcentrated. The obtained residue was purified by column chromatographyon silica gel (ethyl acetate:methanol=20:1). The obtained compound wastreated with 4N hydrogen chloride in ethyl acetate solution to give thetitle compound (89 mg) having the following physical data.

TLC: Rf 0.56 (ethyl acetate:methanol=10:1);

NMR (CD₃OD): δ 1.60-1.80, 2.10-2.25, 2.14, 3.14, 3.15-3.30, 3.50-3.60,4.30, 4.70, 7.15-7.39, 7.51-7.55, 7.68, 7.96, 8.00, 8.22.

Biological Examples

It is proved by the following experiment that the compound of thepresent invention represented by formula (I) has the antagonisticactivity against chemokine receptor, especially CCR5, and the inhibitoryactivity against cell migration, and also has the proper condition to bea very useful medicament.

Biological Example 1 Antagonistic Activity Test Against CCR5

It can be proved by, for example, the procedure described inJP-A-2004-256531 that the compound of the present invention has theantagonistic activity against CCR5.

Biological Example 2 Cell Migration Test

It was proved by, for example, the following experiment that thecompound of the present invention has the inhibitory activity againstcell migration.

Preparation of PBMC (Peripheral Blood Mononuclear Cell)

Human venous blood (50 mL) collected by using syringe with heparinsodium (final concentration: 10 U/mL, heparin sodium injection 1000U/mL, Shimizu Pharmaceutical Co., Ltd.) was stored into 50 mL of conicaltube made by polypropylene. To a Lymphoprep tube (HYCOMED PHARMA, Cat.No 1019818), 16.5 mL of DPBS (−) (GIBCO, Cat No. 14190-136) and a bloodsample were added, jiggled several times, then centrifuged at 3000 rpmfor 10 minutes at room temperature. About 7 mL of PBMC phase (centerphase) was collected into 50 mL of conical tube made by polypropyleneusing a Pasteur pipette, and DPBS (−) was added to a final concentration(50 mL), than centrifuged at 1200 rpm for 10 minutes at roomtemperature. After removing a supernatant, residue was redissolved with50 mL of DPBS (−). The suspension of the cell was centrifuged at 1500rpm for 3 minutes at room temperature. The supernatant was removed, then3 mL of hemolysis buffer (0.8% NH₄Cl, 0.1% KHCO₃, 1 mmol/L EDTA) wasadded thereto to suspend enough, and then left 2 minutes at roomtemperature. The suspension was added by 30 mL of DPBS (−), centrifugedat 1500 rpm for 3 minutes at room temperature. The supernatant wasremoved to give PBMC.

Culture of Human PBMC

After anti human CD3 antibody OKT3 (Janssen Pharmaceutical K.K., 1μg/mL) coated 24 well plate overnight at 4° C., it was blocked byculture medium (RPMI 1640 (GIBCO, Cat. No. 11875-085), 10% FBS (GIBCO,Cat. No. 112318-028), 1% PSF (GIBCO, Cat. No. 15240-096)) in 30 minutesat 37° C. Prepared human PBMC was seeded into the plate coated by OKT3(2×10⁶ cells/well), cultured in a few days at 37° C. PBMC was collected,and seeded into the plate uncoated by OKT3 (2×10⁶ cells/well) in thepresence of human IL2 (5 ng/mL), then cultured. PBMC was subcultureevery two or three days.

Analysis of Human CCR5 Expression Using FACS

After 10 μL of FITC labeled anti human CCR5 antibody (2D7) (BDPharmingen, Cat. No. 555992) and PE labeled anti human CD45RO antibody(BD Pharmingen, Cat. No. 347967) was added to the human PBMC cultured in1×10⁶ cells, the mixture was shaded 15 minutes or left 30 minutes on theice, then DPBS (GIBCO) was added thereto and washed. The cell wassuspended with 500 μL of DPBS, and then fluorescence intensity wasmeasured by using FACS.

In Vitro Experiment of Cell Migration

50 μL of 5×10⁵ cells of the human PBMC suspension (culture medium) and50 μL of the solution of the test compound (0-2 μmol/L: doubleconcentration of a final concentration) were added to an upper well oftranswell (coster), and 300 μL of 60 nmol/L of the human MIP-1β (Peprotech, Cat. No. 300-09) and 300 μL of a double concentration of thesolution of the test compound were added to a lower well. It wasprepared that a concentration of DMSO in upper well was 0.01%. Thesolution was incubated 1.5 hours in the atmosphere of carbon dioxide gas(37° C., 5% CO₂, degree of humidity: 95%). After the solvent of upperwell was aspirated, 100 μL of 20 μmol/L of EDTA/DPBS (−) was addedthereto, and incubated 30 minutes at 4° C., then centrifuged at 1500 rpmfor 5 minutes. 100 μL of the solution was transferred to white 96 wellplate for fluorescence from lower well by pipetting, an amount of cellswas measured by using Celltiter Glo (Promega) (a measurement of ATP),Cell migration inhibition ratio was calculated by the followingcalculating formula. The value of IC₅₀ was calculated from cellmigration inhibition ratio of each concentration. The value was anaverage value (n=3).

As a result, the compounds of the present invention showed inhibitoryactivity against human MIP-1β-induced cell migration of human culturedPBMC with an IC₅₀ value of 0.01 μM or less. For example, the compoundprepared in Example 7(29) showed an IC₅₀ value of 0.0012 μM.

Cell migration inhibition ratio=(Ea−Ec)/(Eb−Ec)×100

-   -   Ea: measured value when a test compound (0.01% in DMSO) is added    -   Eb: measured value when no test compound but only DMSO is added    -   Ec: measured value when no test compound but only DMSO is added        with no added ligand to lower well

Biological Example 3 Stability Test in Liver Microsome of Monkey

It was demonstrated that the compounds of the present invention havemetabolic stability by the following experiments, for example.

To a solution of 100 mmol/L phosphate buffer (pH 7.4, it was preparedfrom 100 mmol/L of aqueous solution of dipotassium hydrogen phosphateand 100 mmol/L of aqueous solution of potassium dihydrogen phosphate),liver microsome of monkey (final concentration: 1 mg/mL) and a testcompound (final concentration: 5 μmol/L) was added and the mixturesolution was pre-incubated for 5 minutes. The mixture solution was addedby NADPH generating system (13 mmol/L β-NADP⁺ (final concentration: 1.3mmol/L), 33 mmol/L G-6-P (final concentration: 3.3 mmol/L), 10 U/mLG-6-P DH (from Yeast) (final concentration: 0.4 U/mL), and 33 mmol/Lmagnesium chloride solution (final concentration: 3.3 mmol/L)). Whilethe mixture was incubated at 37° C., 100 μL of the reaction solution wastaken out 0 and 30 minutes after the start, and was added toacetonitrile (2 mL) to terminate the reaction (n=2). After internalstandard solution was added thereto, the mixture solution was agitated,and then centrifuged at 3000 rpm for 5 minutes. 100 μL of the resultingsupernatant was mixed with 100 μL of mobile phase A, and then wasanalyzed by LC/MS/MS.

The condition of LC/MS/MS for analysis is outlined below.

LC Condition:

-   Column: XTerra RP8 3.5 μm (2.1 mmID×50 mm) (Waters Corporation)-   Temperature of column: 40° C.-   Mobile phase A: 5 mmol/L aqueous ammonium acetate    solution/acetonitrile (80/20, V/V)-   Mobile phase B: 5 mmol/L aqueous ammonium acetate    solution/acetonitrile (20/80, V/V)-   Temperature of sample: 4° C.-   Injection volume of sample: 5 μL-   Time for analysis: 10 min-   Composition of mobile phases, and Flow rate:

TABLE 1 Time (min) Flow rate (μL/min) A (%) B (%) 0.00 300 95.0 5.0 1.00300 95.0 5.0 1.10 300 5.0 95.0 5.00 300 5.0 95.0 5.10 300 95.0 5.0 10.00300 95.0 5.0

MS/MS Condition:

-   Measuring equipment: API3000 (AB/MDS SCIEX)-   Ionization method: Electrospray ionization (ESI, Positive)

The appropriate monitoring ion was selected for an each sample. Forexample, 647.5 (m/z) as parent ion and 277.0 (m/z) as daughter ion wereselected for the compound prepared in Example 7(83).

The residual ratio of the unmetabolite (%) of the test compound in livermicrosome of monkey was calculated by the following calculation formula.

The residual ratio of the unmetabolite(%)=(a concentration of the testcompound at 30 minutes)/(a concentration of the test compound at 0minute)×100

As a result, it was proven that the compounds of the present inventionare metabolic stable in liver microsome. For example, the residual ratioof the unmetabolite of the compound prepared in Example 7(83) was 88%.

Biological Example 4 Pharmacokinetics Test in Blood in Monkey

It was demonstrated that the compounds of the present invention have agood property of pharmacokinetics in blood by the following experiments,for example.

Each of five test compounds were weighed, and dissolved in Soltol(Trademark; BASF Takeda Vitamins Ltd.)/propylene glycol=7/3 heated to50° C. to be 5 mg/mL solution thereof. Equal amount of each five sampleswere weighed, mixed, and then diluted with distilled water for injectionby five times to make a solution for oral administration. The solutionfor oral administration (1 mg/kg) was forced intragastric administeringto cynomolgus monkey (male, Hamri Co., Ltd) with sonde (n=3). Theadministering was done in the fasting state but they have freedom todrink water. Each 1 mL of blood samples were collected from superficialcephalic vein, using a heparinized syringe, 5, 15, 30 minutes, 1, 2, 4,6, 8 and 24 hours after administration. Collected samples were storedinto ice, centrifuged at 3000 rpm for 15 minutes to get plasma. Theplasma was stored at −20° C. The plasma sample stored at −20° C. wasdissolved, then 100 μL of the resulting solution was added by internalstandard solution and acetonitrile (2 mL), agitated, centrifuged at 3000rpm for 10 minutes. The resulting supernatant was dried with acentrifuge concentrator. The residue was redissolved in 100 μL of mobilephase A, and then 40 μL of the resulting solution was analyzed byLC/MS/MS

The condition of LC/MS/MS for analysis is outlined below.

LC Condition:

-   Measuring equipment: Waters 2790 (Waters)-   Column: YMC-Pack MB-ODS 5 μm (2.1 mmID×50 mm) (YMC)-   Temperature of column: room temperature-   Flow rate: 200 μL/minute-   Mobile Phase: 20 mmol/L aqueous ammonium acetate    solution/acetonitrile (1/1, V/V)

MS/MS Condition:

-   Measuring equipment: QUATTRO Ultima (Micromass)-   Ionization method: ES+-   Capillary voltage: 3.20 kV-   Temperature of source: 150° C.-   Temperature of desolvation: 250° C.-   Multiplier: 650V

The appropriate monitoring ion was selected for an each sample. Forexample, 575.64 (m/z) as parent ion and 262.07 (m/z) as daughter ion forthe compound prepared in Example 6(17), and 587.20 (m/z) as parent ionand 227.12 (m/z) as daughter ion for the compound prepared in Example7(54) were selected, respectively.

Transition of plasma concentration of the test compound in monkey wasanalyzed with non-compartment analytic method using WinNonlin 4.0.1(Pharsight), and AUC was calculated.

As a result, it was proven that the compounds of the present inventionhave a good property of pharmacokinetics in blood. For example, the AUCof the compound prepared in Examples 6(17) and 7(54) were 226 ng·h/mLand 1150 ng·h/mL, respectively.

Biological Example 5 Measurement of Bioavailability (BA)

It was demonstrated that the compounds of the present invention havegood absorption of oral preparations by the following experiments, forexample.

The test compound was weighed, and dissolved in 30% HP-β-CD (Trademark;Mitsubishi Corporation) to make 1 mg/mL solution for intravenousadministration. The test compound was weighed, and dissolved in Soltol(Trademark; BASF Takeda Vitamins Ltd.)/propylene glycol=7/3 heated to50° C. to be 5 mg/mL solution thereof. Equal amount of each five sampleswere weighed, mixed, and then diluted with distilled water for injectionby five times to make a solution for oral administration. The solutionfor intravenous administration (1 mg/kg) was administered to cynomolgusmonkey (male, Hamri Co., Ltd) via superficial cephalic vein by singleintravenous dose (n=3). The solution for oral administration (3 mg/kg)was forced intragastric administering to cynomolgus monkey (male, HamriCo., Ltd) with sonde (n=3). The administering was done in the fastingstate but they have freedom to drink water. Each 1 mL of blood sampleswere collected from superficial cephalic vein, using a heparinizedsyringe, 5, 15, 30 minutes, 1, 2, 4, 6, 8 and 24 hours afteradministration. Collected samples were stored into ice, centrifuged at3000 rpm for 15 minutes to get plasma. The plasma was stored at −20° C.The plasma sample stored at −20° C. was dissolved, then 100 μL of theresulting solution was added by internal standard solution andacetonitrile (2 mL), agitated, centrifuged at 3000 rpm for 10 minutes.The residue was redissolved in 100 μL of mobile phase A, and then 40 μLof the resulting solution was analyzed by LC/MS/MS

The condition of LC/MS/MS for analysis is outlined below.

LC Condition:

-   Measuring equipment: Waters 2790 (Waters)-   Column: YMC-Pack MB-ODS 5 μm (2.1 mmID×50 mm) (YMC)-   Temperature of column: room temperature-   Flow rate: 200 μL/minute-   Mobile phase: 20 mmol/L aqueous ammonium acetate    solution/acetonitrile (1/1)

MS/MS Condition:

-   Measuring equipment: QUATTRO Ultima (Micromass)-   Ionization method: ES+-   Capillary voltage: 3.20 kV-   Temperature of source: 150° C.-   Temperature of desolvation: 250° C.-   Multiplier: 650 V

The appropriate monitoring ion was selected for an each sample. Forexample, 575.64 (m/z) as parent ion and 262.07 (m/z) as daughter ion(cone current: 35V, collision current: 34 eV) were selected for thecompound prepared in Example 6(17).

Transition of plasma concentration of the test compound in monkey wasanalyzed with non-compartment analytic method using WinNonlin 4.0.1(Pharsight), and AUC was calculated.

BA was calculated by the following calculation formula.

BA(%)=(AUC_(p.o.)/Dose_(p.o.))/(AUC_(i.v.)/Dose_(i.v.))×100

AUC_(p.o.): AUC when a test compound is orally administered

Dose_(p.o.): amount of the compound administered orally

AUC_(i.v.): when a test compound is intravenously administered

Dose_(i.v.): amount of the compound administered intravenously

As a result, it was proven that the compounds of the present inventionhave good absorption of oral preparations. For example, a BA of thecompound prepared in Example 6(17) was 42%.

Biological Example 6 Model of Renal Allotransplantation in CynomolgusMonkeys to Evaluate Immunosuppressive Effect of the Compound of thePresent Invention

Cynomolgus monkeys (body weight: 3-4.5 kg) that were ABO-compatible,major histocompatibility complex (MHC)-different, more specifically, MLRmiss-matched donor (male)-recipient (either sex) combinations underwentbilateral nephrectomy with subsequent implantation of an allogenickidney from a selected donor animal. A test substance (a compound of thepresent invention and/or an immunosuppressant agent) was administereddaily starting on Day-1 (the day before transplantation) until the daybefore rejection was defined. The efficacy was assessed by comparing thelength of the survival of the transplanted kidney.

The compound of the present invention was administered in combinationwith subtherapeutic immunosuppressant agent on the market (Cyclosporine,sirolimus, and/or tacrolimus). The efficacy was demonstrated bycomparing with administration of immunosuppressant agent alone.

The compound of the present invention was administered, for example, peros (PO), twice a day at a dose level of 3, 10 or 30 mg/kg.

For example, the presence of rejection was suspected if the serumcreatinine levels rise. In particular, rejection of transplanted kidneywas defined as an increase in the serum creatinine levels to 8 mg/dL.

As a result, the compound of the present invention showed animmunosuppressive effect in the model of renal allotransplantation incynomolgus monkeys.

Formulation Examples Formulation Example 1

N′-(4-fluorophenyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]pyridin-3-yl}methyl)piperidin-4-yl]-N-phenylureahydrochloride (10 g), calcium carboxymethyl cellulose (disintegrant, 2.0g), magnesium stearate (lubricant, 1.0 g) and microcrystalline cellulose(87 g) are admixed in a conventional manner, punched them out to give1000 tablets each containing 10 mg of active ingredient.

Formulation Example 2

N′-(4-fluorophenyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]pyridin-3-yl}methyl)piperidin-4-yl]-N-phenylureahydrochloride (10 g), mannitol (200 g) and distilled water (5 L) areadmixed in a conventional manner. Then the solution was filtered througha dustproofing filter, and then 5 ml aliquots were charged intoampoules, which were autoclaved to give 1000 ampoules each containing 10mg of active ingredient.

INDUSTRIAL APPLICABILITY

The compounds of the present invention represented by formula (I) hasthe antagonistic activity against chemokine receptor, especially CCR5,so they are useful in preventing and/or treating CCR5-related diseases,for example, various inflammatory diseases (asthma, nephritis,nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis,conjunctivitis, inflammatory bowel disease such as ulcerative colitis,etc.), immunological diseases (autoimmune diseases, rejection in organtransplantation (rejection of graft of solid organ, rejection of graftof pancreatic islet cells in therapy for diabetes, graft-versus-hostdisease, etc.), immunosuppression, psoriasis, multiple sclerosis, etc.),infectious diseases (infection with human immunodeficiency virus,acquired immunodeficiency syndrome, infection with RSV, etc.), allergicdiseases (atopic dermatitis, urticaria, allergic bronchoplumonaryaspergillosis, allergic eosinophilic gastroenteritis, etc.),cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury,etc.), acute respiratory distress syndrome, shock accompanying bacterialinfection, diabetes, cancer metastasis and so on. Therefore, chemokinereceptor antagonist, especially CCR5 antagonist, is useful asmedicament.

1-33. (canceled)
 34. A compound selected from the group consisting of(1)N-[6-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-pyridinyl]methanesulfonamide,(3)N-{4-[4-({4-[{[(2-hydroxybutyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(4)N-{4-[4-({4-[butyl({[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(5)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-methylbenzamide,(6)N-{4-[4-({4-[{[(4-hydroxycyclohexyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(7) N-[4-(4-{[4-(3-butenyl{[(2-hydroxybutyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,(8)N-butyl-N′-(2,4-difluorophenyl)-N-(1-{4-[4-(4-morpholinylsulfonyl)phenoxy]benzyl}-4-piperidinyl)urea,(9)N-butyl-2-(2,4-difluorophenyl)-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]acetamide,(10)N-{4-[(5-{[4-(butyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(11)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfanyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(12)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfanyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(13)N-butyl-2,4-difluoro-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]benzamide,(14)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfinyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(15)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfinyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(16)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfonyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(17)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfonyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(18)N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-methoxyphenyl]methanesulfonamide,(21)5-[({butyl[1-(4-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(22)5-[({butyl[1-(4-{2-chloro-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(23)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-(2-hydroxyethyl)benzenesulfonamide,(24)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzenesulfonamide,(25)N-{4-[4-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(26)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-methylbenzenesulfonamide,(27)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N,N-dimethylbenzenesulfonamide,(28)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-(2-methoxyethyl)benzenesulfonamide,(31)N-[5-(4-{[4-(butyl[{(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-2-pyridinyl]methanesulfonamide,(32)5-({[butyl(1-{4-[4-(4-morpholinylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(34)5-[({butyl[1-(4-{2,6-dimethyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(35)5-[({butyl[1-(4-{4-[methyl(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(36)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]benzyl}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(37)5-{[(butyl{1-[(3,5-dimethyl-1-{4-[(methylsulfonyl)amino]phenyl}-1H-pyrazol-4-yl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,(38)5-({[(1-{4-[4-(aminosulfonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(39)5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(40)5-[({butyl[1-(4-{4-[(dimethylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(41)N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-methylphenyl]methanesulfonamide,(42)5-[({butyl[1-(4-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(43)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]benzoicacid, (46)5-({[butyl(1-{4-[4-(methylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(47)4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]benzoicacid, (48)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoicacid, (49)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-chlorobenzoicacid, (50)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-nitrobenzoicacid, (51)5-[({butyl[1-(4-{3-methoxy-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(52)5-[({butyl[1-(4-{3-chloro-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(55)N-(4-{4-[(4-{phenyl[(tetrahydro-2H-pyran-4-ylamino)carbonyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(56)5-{[(butyl{1-[(5-{4-[(methylsulfonyl)amino]phenoxy}-2-pyrazinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,(57)5-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-2-[(methylsulfonyl)amino]benzoicacid, (58)2-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzoicacid, (59)N-[4-(4-{[4-(butyl{[(3,4-dicyanophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,(60)N-[4-(4-{[4-(butyl{[(4-cyano-2,5-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,(62)3-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,(63)4-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]benzamide,(64)N-{4-[4-({4-[butyl({[2,4-difluoro-5-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(65)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-(2-methoxyethyl)benzamide,(66)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N,N-dimethylbenzamide,(67)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-(2-hydroxyethyl)benzamide,(68)N-{4-[(5-{[4-(butyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3-chlorophenyl}methanesulfonamide,(69)N-{4-[(5-{[4-(butyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3,5-dimethylphenyl}methanesulfonamide,(72)5-[({2-butynyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(73)2,4-difluoro-5-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](propyl)amino]carbonyl}amino)benzamide,(74)N-{4-[4-({4-[butyl({[2,4-difluoro-5-(hydroxymethyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(77)N-(4-{[5-({4-[{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}(pentyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(78)N-{4-[(5-{[4-(butyl{[(1-ethyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(100)N-[4-(4-{[4-(butyl{[(1,5-dimethyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,(101)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzenesulfonamide,(103)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-N-[2-(dimethylamino)ethyl]-2,4-difluorobenzamide,(105) methyl4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoate,(107) methylN-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)piperidin-1-yl]methyl}phenoxy)phenyl]-N-(methylsulfonyl)glycinate,(108) methylN-{4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]piperidin-1-yl}methyl)phenoxy]phenyl}-N-(methylsulfonyl)glycinate,(116)5-({[(1-{4-[4-(aminocarbonyl)-2-methoxyphenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(117)5-{[(butyl{1-[4-(2-methoxy-4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)benzyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,(118)5-({[butyl(1-{4-[2-methoxy-4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(119)[[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl](methylsulfonyl)amino]aceticacid, (120)[{4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}(methylsulfonyl)amino]aceticacid, (122)5-({[(1-{4-[4-(aminocarbonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(123)5-({[butyl(1-{4-[4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(124)2-{5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorophenyl}acetamide,(157)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamide,(158)N-(4-{[5-({4-[[(cyclohexylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(159)N-[4-({5-[(4-{phenyl[(3-thienylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,(161)N-(4-{[5-({4-[[(benzylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(162)N-{4-[(5-{[4-(phenyl{[(2-phenylethyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(164)N-[4-({5-[(4-{3-thienyl[(3-thienylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,(178)4-fluoro-N-{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}-N-phenylbenzamide,(179)N-[4-({5-[(4-{phenyl[(3-pyridinylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,(180)N-(4-{[5-({4-[(aminocarbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(188)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(190)N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]phenyl}methanesulfonamide,(191)4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]-N-[2-(4-morpholinyl)ethyl]benzenesulfonamide,(208)2-chloro-5-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,(212)2-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,(224)N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(225)N-(3-fluorophenyl)-N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea,(226)N-(3-fluorophenyl)-N-[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N′-(6-methyl-3-pyridinyl)urea,(230)2-[4-({4-[[({4-fluoro-3-[(methylsulfonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,(233)N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylurea,(234)2-[4-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,(235)N-(3-methyl-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(236)N-(3-chloro-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(237)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)ethanesulfonamide,(238)N-{4-[(5-{[4-((3-methylphenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(243)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamide,(245)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-azepanyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(246)N-(4-{[5-({(3R)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(247)N-(4-{[5-({(3S)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(252)N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}ethanesulfonamide,(253)2-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]benzamide,and (254)2-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-[(methylsulfonyl)amino]benzamide,or a salt thereof.
 35. The compound according to claim 34, which isselected from the group consisting of: (5)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-methylbenzamide,(8)N-butyl-N′-(2,4-difluorophenyl)-N-(1-{4-[4-(4-morpholinylsulfonyl)phenoxy]benzyl}-4-piperidinyl)urea,(11)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfanyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(12)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfanyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(14)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfinyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(15)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfinyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(16)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[4-(methylsulfonyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(17)N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[3-(methylsulfonyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(18)N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-methoxyphenyl]methanesulfonamide,(21)5-[({butyl[1-(4-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(22)5-[({butyl[1-(4-{2-chloro-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(23)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-(2-hydroxyethyl)benzenesulfonamide,(24)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzenesulfonamide,(25)N-{4-[4-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(26)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-methylbenzenesulfonamide,(27)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N,N-dimethylbenzenesulfonamide,(28)4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-(2-methoxyethyl)benzenesulfonamide,(32)5-({[butyl(1-{4-[4-(4-morpholinylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(34)5-[({butyl[1-(4-{2,6-dimethyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(35)5-[({butyl[1-(4-{4-[methyl(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(36)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]benzyl}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(38)5-({[(1-{4-[4-(aminosulfonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(39)5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(40)5-[({butyl[1-(4-{4-[(dimethylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(41)N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-methylphenyl]methanesulfonamide,(42)5-[({butyl[1-(4-{2-methyl-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(43)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]benzoicacid, (46)5-({[butyl(1-{4-[4-(methylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(47)4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]benzoicacid, (48)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoicacid, (49)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-chlorobenzoicacid, (50)4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-nitrobenzoicacid, (51)5-[({butyl[1-(4-{3-methoxy-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(52)5-[({butyl[1-(4-{3-chloro-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(57)5-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-2-[(methylsulfonyl)amino]benzoicacid, (58)2-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzoicacid, (59)N-[4-(4-{[4-(butyl{[(3,4-dicyanophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,(60)N-[4-(4-{[4-(butyl{[(4-cyano-2,5-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,(62)3-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,(63)4-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]benzamide,(64)N-{4-[4-({4-[butyl({[2,4-difluoro-5-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(65)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-(2-methoxyethyl)benzamide,(66)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N,N-dimethylbenzamide,(67)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-(2-hydroxyethyl)benzamide,(72)5-[({2-butynyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,(73)2,4-difluoro-5-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](propyl)amino]carbonyl}amino)benzamide,(74)N-{4-[4-({4-[butyl({[2,4-difluoro-5-(hydroxymethyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(101)4-(4-{[4-(butyl[{(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzenesulfonamide,(103)5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-N-[2-(dimethylamino)ethyl]-2,4-difluorobenzamide,(105) methyl4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoate,(107) methylN-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)piperidin-1-yl]methyl}phenoxy)phenyl]-N-(methylsulfonyl)glycinate,(108) methylN-{4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]piperidin-1-yl}methyl)phenoxy]phenyl}-N-(methylsulfonyl)glycinate,(116)5-({[(1-{4-[4-(aminocarbonyl)-2-methoxyphenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(117)5-{[(butyl{1-[4-(2-methoxy-4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)benzyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,(118)5-({[butyl(1-{4-[2-methoxy-4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(119)[[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl](methylsulfonyl)amino]aceticacid, (120)[{4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}(methylsulfonyl)amino]aceticacid, (122)5-({[(1-{4-[4-(aminocarbonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(123)5-({[butyl(1-{4-[4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,(124)2-{5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorophenyl}acetamide,(208)2-chloro-5-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,(212)2-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,(230)2-[4-({4-[[({4-fluoro-3-[(methylsulfonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,and (234)2-[4-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,or a salt thereof.
 36. The compound according to claim 34, which isselected from the group consisting of: (37)5-{[(butyl{1-[(3,5-dimethyl-1-{4-[(methylsulfonyl)amino]phenyl}-1H-pyrazol-4-yl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,(190)N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]phenyl}methanesulfonamide,and (191)4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-3,5-dimethyl-1H-pyrazol-1-yl]-N-[2-(4-morpholinyl)ethyl]benzenesulfonamide,or a salt thereof.
 37. The compound according to claim 34, which isselected from the group consisting of: (56)5-{[(butyl{1-[(5-{4-[(methylsulfonyl)amino]phenoxy}-2-pyrazinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-difluorobenzamide,and (157)N-(4-{[5-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamide,or a salt thereof.
 38. The compound according to claim 34, which isselected from the group consisting of: (1)N-[6-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-pyridinyl]methanesulfonamide,(3)N-{4-[4-({4-[{[(2-hydroxybutyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(4)N-{4-[4-({4-[butyl({[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(6)N-{4-[4-({4-[{[(4-hydroxycyclohexyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,(7)N-[4-(4-{[4-(3-butenyl{[(2-hydroxybutyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,(9)N-butyl-2-(2,4-difluorophenyl)-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]acetamide,(10)N-{4-[(5-{[4-(butyl[{(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(13)N-butyl-2,4-difluoro-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]benzamide,(31)N-[5-(4-{[4-(butyl[{(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-2-pyridinyl]methanesulfonamide,(55)N-(4-{4-[(4-{phenyl[(tetrahydro-2H-pyran-4-ylamino)carbonyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide,(68)N-{4-[(5-{[4-(butyl[{(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3-chlorophenyl}methanesulfonamide,(69)N-{4-[(5-{[4-(butyl[{(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3,5-dimethylphenyl}methanesulfonamide,(77)N-(4-{[5-({4-[{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl}(pentyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(78)N-{4-[(5-{[4-(butyl{[(1-ethyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(100)N-[4-(4-{[4-(butyl{[(1,5-dimethyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,(158)N-(4-{[5-({4-[[(cyclohexylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(159)N-[4-({5-[(4-{phenyl[(3-thienylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,(161)N-(4-{[5-({4-[[(benzylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(162)N-{4-[(5-{[4-(phenyl{[(2-phenylethyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(164)N-[4-({5-[(4-{3-thienyl[(3-thienylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,(178)4-fluoro-N-{1-[(6-{4-[(methylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}-N-phenylbenzamide,(179)N-[4-({5-[(4-{phenyl[(3-pyridinylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,(180)N-(4-{[5-({4-[(aminocarbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(188)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(224)N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(225)N-(3-fluorophenyl)-N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea,(226)N-(3-fluorophenyl)-N-[1-({6-[2-methoxy-4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N′-(6-methyl-3-pyridinyl)urea,(233)N′-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-phenylurea,(235)N-(3-methyl-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(236)N-(3-chloro-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(237)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)ethanesulfonamide,(238)N-{4-[(5-{[4-((3-methylphenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,(243)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamide,(245)N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-azepanyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(246)N-(4-{[5-({(3R)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(247)N-(4-{[5-({(3S)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,(252)N-{4-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}ethanesulfonamide,(253)2-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulfonyl)amino]benzamide,and (254)2-[(5-{[4-((3-fluorophenyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-[(methylsulfonyl)amino]benzamide,or a salt thereof.
 39. A pharmaceutical composition, which comprises thecompound according to any one of claims 34 to 38, or a salt thereof.